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Trivedi, V.S.;  Magnusen, A.F.;  Rani, R.;  Marsili, L.;  Slavotinek, A.M.;  Prows, D.R.;  Hopkin, R.J.;  Mckay, M.A.;  Pandey, M.K. Complement–Sphingolipid System in COVID-19 and Gaucher Diseases. Encyclopedia. Available online: (accessed on 11 December 2023).
Trivedi VS,  Magnusen AF,  Rani R,  Marsili L,  Slavotinek AM,  Prows DR, et al. Complement–Sphingolipid System in COVID-19 and Gaucher Diseases. Encyclopedia. Available at: Accessed December 11, 2023.
Trivedi, Vyoma Snehal, Albert Frank Magnusen, Reena Rani, Luca Marsili, Anne Michele Slavotinek, Daniel Ray Prows, Robert James Hopkin, Mary Ashley Mckay, Manoj Kumar Pandey. "Complement–Sphingolipid System in COVID-19 and Gaucher Diseases" Encyclopedia, (accessed December 11, 2023).
Trivedi, V.S.,  Magnusen, A.F.,  Rani, R.,  Marsili, L.,  Slavotinek, A.M.,  Prows, D.R.,  Hopkin, R.J.,  Mckay, M.A., & Pandey, M.K.(2022, November 25). Complement–Sphingolipid System in COVID-19 and Gaucher Diseases. In Encyclopedia.
Trivedi, Vyoma Snehal, et al. "Complement–Sphingolipid System in COVID-19 and Gaucher Diseases." Encyclopedia. Web. 25 November, 2022.
Complement–Sphingolipid System in COVID-19 and Gaucher Diseases

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced disease (COVID-19) and Gaucher disease (GD) exhibit upregulation of complement 5a (C5a) and its C5aR1 receptor, and excess synthesis of glycosphingolipids that lead to increased infiltration and activation of innate and adaptive immune cells, resulting in massive generation of pro-inflammatory cytokines, chemokines and growth factors. This C5a–C5aR1–glycosphingolipid pathway- induced pro-inflammatory environment causes the tissue damage in COVID-19 and GD. Strikingly, pharmaceutically targeting the C5a–C5aR1 axis or the glycosphingolipid synthesis pathway led to a reduction in glycosphingolipid synthesis and innate and adaptive immune inflammation, and protection from the tissue destruction in both COVID-19 and GD. 

lipid viral infection rare-genetic disease innate and adaptive immunity inflammation

1. Introduction

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)-induced Disease (COVID-19) displays complement activation products (Table 1) and excess formation of sphingolipids [1][2][3][4]. Additionally, SARS-CoV-2 triggers infiltration and activation of several classes of innate and adaptive immune cells, as well as the abnormal production of pro-inflammatory cytokines, chemokines, and growth factors in COVID-19 (Table 1 and Table 2). Such SARS-CoV-2-induced immune inflammation affects multiple organs (i.e., lung, liver, spleen, cardiovascular system, and brain) and causes the development of moderate (e.g., high fever, shortness of breath, loss of taste and/or smell, sore throat, nausea, and vomiting) to severe (e.g., pneumonia, bronchitis, respiratory failure, lung damage and death) symptoms of COVID-19 [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23].
Table 1. Immune cells and their effector inflammatory mediators in COVID-19.
Coronavirus Immune Cell
Source Changes in
Products, Cytokines
and Chemokines
SARS-CoV-2 Leucocytes, PMNs
Endothelial cells
C5a +++
C5aR1 +++
MAC +++
SARS-CoV-2 Type-II pneumocytes Pulmonary cells
C1q P+++
C3b-regulatory factor H (FH) P+++
C3 P+++
SARS-CoV-2 Type-II pneumocytes PBMCs Blood
C3a P+++
C3aR P +++
C3b-CD46 P+++
SARS-CoV-2 PBMCs Blood
sC5b-9 P+++ [27][35][36][37]
SARS-2 Respiratory specimen cells
Alveolar cells
C4d P+++ [35][38]
SARS-CoV-2 Respiratory
specimen cells
C3bBbP P+++ [35]
SARS-CoV-2 Respiratory
specimen cells
C3bc P+++ [35]
Cardiac Microthrombi
and Alveolar cells
Blood Sera
C5b-C9 P+++ [36][37][38][39][40]
SARS-CoV-2 Pulmonary cells Lung C1r P+++ [29]
SARS-CoV-1 Pulmonary cells Lung iC3b P+++ [31]
SARS-CoV-1 Pulmonary cells Lung C3c P++ [31]
SARS-CoV-1 Pulmonary cells Lung C3dg P+++ [31]
T cells
IL12 M+++
IL8 M+++
TNFα M+++
IL-6 M&P+++
IFNλ M+++
CXCL10 M&P+++
CCL2 M+++
CCL3 M+++
CCL5 M+++
IFNα M+ & P+++
IFNβ M+ & P+++
SARS-CoV-1 Mos
Cord blood cells
TNFα M+++
IFNλ M+++
IL8 M+++
TNFα M+++
IL6 M+++
CCL2 M+++
CCL3 M+++
CCL5 M+++
Blood IL6 P+++
IL8 P+++
IL10 P+++
TNFα P+++
SARS-CoV-2 CD8+ cells
NK+ cells
IFNγ P+++
Granzyme B P+++
SARS-CoV-2 CD8+ cells
CD4+ cells
Cytokines NR [53]
SARS-CoV-2 PMNs Lung Cytokines NR [54]
MERS CD4+ T cells
CD8+ T cells
Lymph Nodes
Caspase-3 P+++ [55]
SARS-CoV-1 CD4+ cells
CD8+ cells
CD45RO+ and
CD27+ cells
TNFα P++
IFNγ P+++
SARS-CoV-2 CD4+ T cells
CD8+ T cells
Regulatory T cells
Perforin P+++
IL6 P+++
IL2 M+++
IL7 M+++
MERS Epithelial cells Lung IL1β M+++
IL6 M+++
IL8 M+++
SARS-CoV-1 Epithelial cells Lung TNFα M+++
IFNβ M+++
CXCL10 M+++
COVID-19 (Coronavirus disease 2019), MERS-CoV (Middle East Respiratory Syndrome Coronavirus), SARS-CoV-1 (Severe Acute Respiratory Syndrome Coronavirus-1), SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), AECs (Airway epithelial cells), Mɸs (Macrophages), DCs (Dendritic cells), PMNs (Polymorphonuclear cells), NK (Natural Killer cells), IFN (interferon), α (alpha), β (beta), γ(gamma), λ (lambda), IL (interleukin), TNF (tumor necrosis factor), CCL (Chemokine (C-C motif) ligand), CXCL (Chemokine (C-X-C motif) ligand), PBMCs (Peripheral Blood Mononuclear Cells), PCs (Pulmonary Cells), MAC (Membrane Attack Complex; MAC), C3a (Complement 3a), C3b (Complement 3b), C3aR (Complement 3a Receptor), C5a (Complement 5a), C5aR1 (C5a Receptor 1), sC5b-9 (soluble C5b-9; MAC); C4d (Complement 4d). C3bBbP (complement 3 b bound protease fragment), C3bc (Complement 3 bc), P (Protein expression level), M (mRNA expression level) + (low), ++ (moderate), and +++ (high), NS (not significant).
Increased levels of complement activation products have been linked to innate and adaptive immune cell activation and increased production of pro-inflammatory cytokines, chemokines, and growth factors in GD (Table 3). The excess tissue and cellular accumulation of glucosylceramides (GCs) and their subsequent roles in the induction of innate and adaptive immune inflammation significantly affect visceral organs (e.g., liver, spleen, lung, bone, and kidney) and the central nervous system (CNS), causing the development of GD manifestations characterized by anemia, thrombocytopenia, hypergammaglobulinemia, splenomegaly, hepatomegaly, respiratory distress, skeletal weakness, loss of neurons, and death [66][67][68][69][70][71][72][73][74][75][76].

2. COVID-19

COVID-19 is caused by infection with SARS-CoV-2, a member of the family of betacoronaviruses that also includes the SARS-CoV-1 and Middle East Respiratory Syndrome-CoV (MERS-CoV) [77][78]. SARS-CoV-2 is a large, enveloped, single-stranded positive-sense RNA virus with a genome size of about 30 kb. The 5′ end of the SARS-CoV-2 genome encodes two polyproteins termed PP1a and PP1ab, which are mutually called replicases. These polyproteins are classified with 16 non-structural proteins, including RNA-dependent RNA polymerase (RDRP), 3-chymotrypsin-like protease (3CLP), and papain-like protease (PLP). The 3′ end of the SARS-CoV-2 genome encodes four essential structural proteins: spike (S; essential for the viral entry into host cells), envelope (E; responsible for viral membrane twist and binding to the nucleocapsid), membrane (M; bind to the viral RNA genome and guarantee the conservation of the RNA in the shape of the beads-on-a-string) and the nucleocapsid (N; required for viral replication and pathogenesis of the disease). The 3′ end also encodes non-structural proteins, including PLP, 3CLP, RDRP, helicase, and the collection of accessory proteins, which affect the host-specific immune reactions [79][80][81]. The S protein is critical for the infectivity of SARS-CoV-2 and is cut by a host protease into the S1 and S2 subunits. The S1 subunit binds to angiotensin converting enzyme-2 (ACE2), which acts as a protease to cleave angiotensin II and also counteracts the effect of angiotensin II [82][83]. ACE2 is the cellular receptor for SARS-CoV-2 and is widely expressed in blood vessels, tongue, lung, adipose tissue, adrenal gland, heart, esophagus, lung, muscle, ovary [22][84][85][86] and eye tissues (i.e., conjunctiva, choroid, vascular endothelium, and nerves) [87][88][89][90][91].
The S2 subunit is activated by transmembrane protease serine-2 (TMPRSS2) associated with the host surface. These combined actions result in host-viral membrane fusion and SARS-CoV-2 entry into the host cells [92][93]. The viral RNA genome is released into the host cell cytoplasm, where it first uses the host translational machinery for the formation of the viral structural and accessory proteins [79][93]. The newly synthesized structural and accessory proteins are transferred through the endoplasmic reticulum and Golgi bodies followed by assembly of new virions in the growing Golgi vesicles [81]. Finally, similar to the MERS-CoV and SARS-CoV-1, the mature SARS-CoV-2 virions are exocytosed from the host cell into the surrounding environment to repeat the infection cycle. Infection results in activation of innate and adaptive immune cells and a massive generation of several pro-inflammatory mediators (Table 1 and Table 2) that instigate moderate to severe disease symptoms of COVID-19 [14][15][16][17][18][19][20][21][22][23]. The SARS-CoV-2-induced development of COVID-19 disease has been reported in people with immunocompromised and morbid conditions, such as sepsis, acute cardiac injury, heart failure, and multi-organ (e.g., liver, spleen, kidney, and brain) disease [94]. Epidemiological studies related to COVID-19 have found that males are slightly more prone to infection as compared to females, but both sexes experience severe forms of COVID-19 and death. Persons > 60 years old or with chronic diseases, such as type 2 diabetes and essential hypertension, were at higher risk for SARS-CoV-2-induced systemic inflammation leading to a severe form of COVID-19 [95][96][97].
Table 2. Coronavirus-induced production of circulatory cytokines.
Coronavirus Source Cytokines Chemokines Growth Factors References
MERS Sera IFNα P+++
IL6 P+++
IL8 P+++
CCL5 P+++
CXCL10 P+++
SARS-CoV-1 Sera IFNα P+++
IFNγ P+++
IL1 P+++
IL2 P+++
IL6 P+++
IL8 P+++
IL10 P+
IL12 P+++
CCL2 P+++
CXCL9 P+++
CXCL10 P+++
TGFβ P+++ [98][99][100][101][102][103][104][105][106][107][108][109]
SARS-CoV-2 Sera IFNγ P+++
TNFα P+++
IL1b P+++
IL1RA P+++
IL2 P++
IL2R P++
IL4 P++
IL5 P++
IL6 P+++
IL7 P+++
IL8 P+++
IL9 P+++
IL12 P+++
G-CSF P+++
FGF P+++
SARS-CoV-2 Sera   CCL2 P+++   [109][114]
SARS-CoV-2 Sera   CCL3 NS   [109]
SARS-CoV-2 Sera   CXCL8 P+++   [114]
SARS-CoV-2 Sera   CXCL10 P++   [109][114]
MERS-CoV (Middle East Respiratory Syndrome Coronavirus), SARS-CoV-1 (Severe Acute Respiratory Syndrome Coronavirus-1), SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2), IFN (interferon), IL (interleukin), TNF (tumor necrosis factor), CCL (C-C motif ligand), CXCL (C-X-C motif ligand), TGF (transforming growth factor), GCSF (granulocyte colony stimulating factor), GMCSF (granulocyte-Mɸ colony stimulating factor), VEGF (vascular endothelial cell growth factor), FGF (fibroblast growth factor), PDGF (platelet-derived growth factor), α (alpha), β (beta), γ (gamma), λ (lambda), P (Protein expression level), M (mRNA expression level): + (low), ++ (moderate), and +++ (high), NS (not significant).
Table 3. Immune cells involvement in GD.
  Mouse Model of GD GD Patients
Immune Cells Tissue Recruitment References Immune Cells References
MOs Blood +++ [115] Blood - [116][117]
Mɸs Blood +++, Liver +++,
Spleen +++, Lung +++
[66][115][118][119] Lymph node +++ [120]
mDCs Blood +++, Liver +++,
Spleen +++, Lung +++
[66][115][118][119] Blood - [116][117][121][122]
pDCs     Blood - [116][117][121]
PMNs Blood +++, Liver +++,
Spleen +++, Bone Marrow +++
CD4 + TCells Liver +++, Spleen +++, Lung +++ [66][118][119] Blood +++ [121][122]
CD8 + T Cells Thymus +++,
Spleen +++
[118][119] Blood +++ [122][123]
NK Cells     Blood - [121][123]
MOs (Monocytes), Mɸs (Macrophages), mDCs (myeloid dendritic cells), pDCs (plasmacytoid dendritic cells), PMNs (Polymorphonuclear cells), NK (Natural killer cells), Increased (+++) and decreased (-) tissue recruitment.


  1. Wu, D.; Shu, T.; Yang, X.; Song, J.-X.; Zhang, M.; Yao, C.; Liu, W.; Huang, M.; Yu, Y.; Yang, Q.; et al. Plasma metabolomic and lipidomic alterations associated with COVID-19. Natl. Sci. Rev. 2020, 7, 1157–1168.
  2. Vitner, E.B.; Avraham, R.; Politi, B.; Melamed, S.; Israely, T. Elevation in sphingolipid upon SARS-CoV-2 infection: Possible implications for COVID-19 pathology. Life Sci. Alliance 2021, 5, e202101168.
  3. Khodadoust, M.M. Inferring a causal relationship between ceramide levels and COVID-19 respiratory distress. Sci. Rep. 2021, 11, 20866.
  4. Torretta, E.; Garziano, M.; Poliseno, M.; Capitanio, D.; Biasin, M.; Santantonio, T.A.; Clerici, M.; Caputo, S.L.; Trabattoni, D.; Gelfi, C. Severity of COVID-19 Patients Predicted by Serum Sphingolipids Signature. Int. J. Mol. Sci. 2021, 22, 10198.
  5. Russo, F.P.; Burra, P.; Zanetto, A. COVID-19 and liver disease: Where are we now? Nat. Rev. Gastroenterol. Hepatol. 2022, 19, 277–278.
  6. Tahtabasi, M.; Hosbul, T.; Karaman, E.; Akın, Y.; Konukoglu, O.; Sahiner, F. Does COVID-19 cause an increase in spleen dimensions? Possible effects of immune activation, hematopoietic suppression and microthrombosis. Clin. Imaging 2021, 79, 104–109.
  7. Suwaidi, A.S.; Alakasheh, B.J.; Al-Ozaibi, L.S. Splenic Infarction in a COVID-19 Patient without Respiratory Symptoms. Dubai Med. J. 2022, 5, 74–77.
  8. Shaukat, I.; Khan, R.; Diwakar, L.; Kemp, T.; Bodasing, N. Atraumatic splenic rupture due to COVID-19 infection. Clin. Infect. Pract. 2020, 10, 100042.
  9. Xie, Y.; Xu, E.; Bowe, B.; Al-Aly, Z. Long-term cardiovascular outcomes of COVID-19. Nat. Med. 2022, 28, 583–590.
  10. Abbasi, J. Even Mild COVID-19 May Change the Brain. JAMA 2022, 327, 1321–1322.
  11. Douaud, G.; Lee, S.; Alfaro-Almagro, F.; Arthofer, C.; Wang, C.; McCarthy, P.; Lange, F.; Andersson, J.L.R.; Griffanti, L.; Duff, E.; et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 2022, 604, 697–707.
  12. Haj, E.M.; Altintas, E.; Chapelet, G.; Kapogiannis, D.; Gallouj, K. High depression and anxiety in people with Alzheimer’s disease living in retirement homes during the COVID-19 crisis. Psychiatry Res. 2020, 291, 113294.
  13. Lou, J.J.; Movassaghi, M.; Gordy, D.; Olson, M.G.; Zhang, T.; Khurana, M.S.; Chen, Z.; Perez-Rosendahl, M.; Thammachantha, S.; Singer, E.J.; et al. Neuropathology of COVID-19 (neuro-COVID): Clinicopathological update. Free Neuropathol. 2021, 2, 2.
  14. Hui, D.S.; Azhar, E.I.; Madani, T.A.; Ntoumi, F.; Kock, R.; Dar, O.; Ippolito, G.; McHugh, T.D.; Memish, Z.A.; Drosten, C.; et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health—The latest 2019 novel coronavirus outbreak in Wuhan, China. Int. J. Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis. 2020, 91, 264–266.
  15. Guo, Y.-R.; Cao, Q.-D.; Hong, Z.-S.; Tan, Y.-Y.; Chen, S.-D.; Jin, H.-J.; Tan, K.-S.; Wang, D.-Y.; Yan, Y. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak—An update on the status. Mil. Med. Res. 2020, 7, 11.
  16. Luk, H.K.H.; Li, X.; Fung, J.; Lau, S.K.P.; Woo, P.C.Y. Molecular epidemiology, evolution and phylogeny of SARS coronavirus. Infect. Genet. Evol. 2019, 71, 21–30.
  17. Ramadan, N.; Shaib, H. Middle East respiratory syndrome coronavirus (MERS-CoV): A review. Germs 2019, 9, 35–42.
  18. Menachery, V.D.; Yount, B.L., Jr.; Debbink, K.; Agnihothram, S.; Gralinski, L.E.; Plante, J.A.; Graham, R.L.; Scobey, T.; Ge, X.-Y.; Donaldson, E.F.; et al. A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat. Med. 2015, 21, 1508–1513.
  19. Ge, X.-Y.; Li, J.-L.; Yang, X.-L.; Chmura, A.A.; Zhu, G.; Epstein, J.H.; Mazet, J.K.; Hu, B.; Zhang, W.; Peng, C.; et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 2013, 503, 535–538.
  20. Hemida, M.G.; Ali, A.M.; Alnaeem, A. The Middle East respiratory syndrome coronavirus (MERS-CoV) nucleic acids detected in the saliva and conjunctiva of some naturally infected dromedary camels in Saudi Arabia-2019. Zoonoses Public Health 2021, 68, 353–357.
  21. Hemida, M.G.; Alhammadi, M.; Almathen, F.; Alnaeem, A. Lack of detection of the Middle East respiratory syndrome coronavirus (MERS-CoV) nucleic acids in some Hyalomma dromedarii infesting some Camelus dromedary naturally infected with MERS-CoV. BMC Res. Notes 2021, 14, 96.
  22. Benito-Pascual, B.; Gegúndez, A.J.; Díaz-Valle, D.; Arriola-Villalobos, P.; Carreño, E.; Culebras, E.; Rodríguez-Avial, I.; Benitez-Del-Castillo, J.M. Panuveitis and Optic Neuritis as a Possible Initial Presentation of the Novel Coronavirus Disease 2019 (COVID-19). Ocul. Immunol. Inflamm. 2020, 28, 922–925.
  23. Pandey, M.K. Pre-existing humoral immune comebacks control the development of the severe form of coronavirus disease 2019 in Gaucher patients. Clin. Transl. Discov. 2022, 2, e96.
  24. Carvelli, J.; Demaria, O.; Vély, F.; Batista, L.; Benmansour, N.C.; Fares, J.; Carpentier, S.; Thibult, M.-L.; Morel, A.; Remark, R.; et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 axis. Nature 2020, 588, 146–150.
  25. Ma, L.; Sahu, S.K.; Cano, M.; Kuppuswamy, V.; Bajwa, J.; McPhatter, J.; Pine, A.; Meizlish, M.L.; Goshua, G.; Chang, C.H.; et al. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci. Immunol. 2021, 6, 1–21.
  26. Afzali, B.; Noris, M.; Lambrecht, B.N.; Kemper, C. The state of complement in COVID-19. Nat. Rev. Immunol. 2021, 22, 77–84.
  27. Cugno, M.; Meroni, P.L.; Gualtierotti, R.; Griffini, S.; Grovetti, E.; Torri, A.; Panigada, M.; Aliberti, S.; Blasi, F.; Tedesco, F.; et al. Complement activation in patients with COVID-19: A novel therapeutic target. J. Allergy Clin. Immunol. 2020, 146, 215–217.
  28. Sinkovits, G.; Mező, B.; Réti, M.; Müller, V.; Iványi, Z.; Gál, J.; Gopcsa, L.; Reményi, P.; Szathmáry, B.; Lakatos, B.; et al. Complement Overactivation and Consumption Predicts In-Hospital Mortality in SARS-CoV-2 Infection. Front. Immunol. 2021, 12, 663187.
  29. Rockx, B.; Baas, T.; Zornetzer, G.A.; Haagmans, B.; Sheahan, T.; Frieman, M.; Dyer, M.D.; Teal, T.H.; Proll, S.; Brand, J.V.D.; et al. Early Upregulation of Acute Respiratory Distress Syndrome-Associated Cytokines Promotes Lethal Disease in an Aged-Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Infection. J. Virol. 2009, 83, 7062–7074.
  30. Perico, L.; Morigi, M.; Galbusera, M.; Pezzotta, A.; Gastoldi, S.; Imberti, B.; Perna, A.; Ruggenenti, P.; Donadelli, R.; Benigni, A.; et al. SARS-CoV-2 Spike Protein 1 Activates Microvascular Endothelial Cells and Complement System Leading to Platelet Aggregation. Front. Immunol. 2022, 13, 827146.
  31. Gralinski, L.E.; Sheahan, T.P.; Morrison, T.E.; Menachery, V.; Jensen, K.; Leist, S.R.; Whitmore, A.; Heise, M.T.; Baric, R.S. Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio 2018, 9, e01753-18.
  32. Ali, Y.M.; Ferrari, M.; Lynch, N.J.; Yaseen, S.; Dudler, T.; Gragerov, S.; Demopulos, G.; Heeney, J.L.; Schwaeble, W.J. Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins. Front. Immunol. 2021, 12, 714511.
  33. Ip, W.K.E.; Chan, K.H.; Law, H.K.-W.; Tso, G.H.W.; Kong, E.K.P.; Wong, H.S.W.; To, Y.F.; Yung, R.W.H.; Chow, E.Y.; Au, K.L.; et al. Mannose-Binding Lectin in Severe Acute Respiratory Syndrome Coronavirus Infection. J. Infect. Dis. 2005, 191, 1697–1704.
  34. Shen, B.; Yi, X.; Sun, Y.; Bi, X.; Du, J.; Zhang, C.; Quan, S.; Zhang, F.; Sun, R.; Qian, L.; et al. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell 2020, 182, 59–72.e15.
  35. Holter, J.C.; Pischke, S.E.; de Boer, E.; Lind, A.; Jenum, S.; Holten, A.R.; Tonby, K.; Barratt-Due, A.; Sokolova, M.; Schjalm, C.; et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc. Natl. Acad. Sci. USA 2020, 117, 25018–25025.
  36. Syrimi, E.; Fennell, E.; Richter, A.; Vrljicak, P.; Stark, R.; Ott, S.; Murray, P.G.; Al-Abadi, E.; Chikermane, A.; Dawson, P.; et al. The immune landscape of SARS-CoV-2-associated Multisystem Inflammatory Syndrome in Children (MIS-C) from acute disease to recovery. iScience 2021, 24, 103215.
  37. Romanova, E.S.; Vasilyev, V.V.; Startseva, G.; Karev, V.; Rybakova, M.G.; Platonov, P.G. Cause of death based on systematic post-mortem studies in patients with positive SARS-CoV-2 tissue PCR during the COVID-19 pandemic. J. Intern. Med. 2021, 290, 655–665.
  38. Magro, C.; Mulvey, J.J.; Berlin, D.; Nuovo, G.; Salvatore, S.; Harp, J.; Baxter-Stoltzfus, A.; Laurence, J. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl. Res. 2020, 220, 1–13.
  39. Pfister, F.; Vonbrunn, E.; Ries, T.; Jäck, H.-M.; Überla, K.; Lochnit, G.; Sheriff, A.; Herrmann, M.; Büttner-Herold, M.; Amann, K.; et al. Complement Activation in Kidneys of Patients With COVID-19. Front. Immunol. 2020, 11, 594849.
  40. Dong, E.; Du, H.; Gardner, L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect. Dis. 2020, 20, 533–534.
  41. Coleman, C.M.; Sisk, J.M.; Halasz, G.; Zhong, J.; Beck, S.E.; Matthews, K.L.; Venkataraman, T.; Rajagopalan, S.; Kyratsous, C.A.; Frieman, M.B. CD8+ T Cells and Macrophages Regulate Pathogenesis in a Mouse Model of Middle East Respiratory Syndrome. J. Virol. 2017, 91, 1–22.
  42. Tynell, J.; Westenius, V.; Rönkkö, E.; Munster, V.; Melén, K.; Österlund, P.; Julkunen, I. Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J. Gen. Virol. 2016, 97, 344–355.
  43. Zhou, J.; Chu, H.; Li, C.; Wong, B.H.-Y.; Cheng, Z.-S.; Poon, V.K.-M.; Sun, T.; Lau, C.C.-Y.; Wong, K.K.-Y.; Chan, J.Y.-W.; et al. Active Replication of Middle East Respiratory Syndrome Coronavirus and Aberrant Induction of Inflammatory Cytokines and Chemokines in Human Macrophages: Implications for Pathogenesis. J. Infect. Dis. 2013, 209, 1331–1342.
  44. Ng, D.L.; Hosani, A.F.; Keating, M.K.; Gerber, S.I.; Jones, T.L.; Metcalfe, M.G.; Tong, S.; Tao, Y.; Alami, N.N.; Haynes, L.M.; et al. Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East Respiratory Syndrome Coronavirus Infection in the United Arab Emirates, April 2014. Am. J. Pathol. 2016, 186, 652–658.
  45. Min, C.-K.; Cheon, S.; Ha, N.-Y.; Sohn, K.M.; Kim, Y.; Aigerim, A.; Shin, H.M.; Choi, J.-Y.; Inn, K.-S.; Kim, J.H.; et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci. Rep. 2016, 6, 25359.
  46. Scheuplein, V.A.; Seifried, J.; Malczyk, A.H.; Miller, L.; Höcker, L.; Vergara-Alert, J.; Dolnik, O.; Zielecki, F.; Becker, B.; Spreitzer, I.; et al. High Secretion of Interferons by Human Plasmacytoid Dendritic Cells upon Recognition of Middle East Respiratory Syndrome Coronavirus. J. Virol. 2015, 89, 3859–3869.
  47. Kim, E.S.; Choe, P.G.; Park, W.B.; Oh, H.S.; Kim, E.J.; Nam, E.Y.; Na, S.H.; Kim, M.; Song, K.-H.; Bang, J.H.; et al. Clinical Progression and Cytokine Profiles of Middle East Respiratory Syndrome Coronavirus Infection. J. Korean Med. Sci. 2016, 31, 1717–1725.
  48. Law, H.K.-W.; Cheung, C.Y.; Ng, H.Y.; Sia, S.F.; Chan, Y.O.; Luk, W.; Nicholls, J.M.; Peiris, J.S.M.; Lau, Y.L. Chemokine up-regulation in SARS-coronavirus–infected, monocyte-derived human dendritic cells. Blood 2005, 106, 2366–2374.
  49. Cheung, C.Y.; Poon, L.; Ng, I.H.Y.; Luk, W.; Sia, S.-F.; Wu, M.H.S.; Chan, K.-H.; Yuen, K.-Y.; Gordon, S.; Guan, Y.; et al. Cytokine Responses in Severe Acute Respiratory Syndrome Coronavirus-Infected Macrophages In Vitro: Possible Relevance to Pathogenesis. J. Virol. 2005, 79, 7819–7826.
  50. Spiegel, M.; Schneider, K.; Weber, F.; Weidmann, M.; Hufert, F.T. Interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells. J. Gen. Virol. 2006, 87, 1953–1960.
  51. Qin, C.; Zhou, L.; Hu, Z.; Zhang, S.; Yang, S.; Tao, Y.; Xie, C.; Ma, K.; Shang, K.; Wang, W.; et al. Dysregulation of Immune Response in Patients with Coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 2020, 71, 762–768.
  52. Zheng, M.; Gao, Y.; Wang, G.; Song, G.; Liu, S.; Sun, D.; Xu, Y.; Tian, Z. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol. Immunol. 2020, 17, 533–535.
  53. Fox, S.E.; Akmatbekov, A.; Harbert, J.L.; Li, G.; Brown, J.Q.; Heide, R.S.V. Pulmonary and cardiac pathology in African American patients with COVID-19: An autopsy series from New Orleans. Lancet Respir. Med. 2020, 8, 681–686.
  54. Barnes, B.J.; Adrover, J.M.; Baxter-Stoltzfus, A.; Borczuk, A.; Cools-Lartigue, J.; Crawford, J.M.; Daßler-Plenker, J.; Guerci, P.; Huynh, C.; Knight, J.S.; et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J. Exp. Med. 2020, 217, e20200652.
  55. Chu, H.; Zhou, J.; Wong, B.H.-Y.; Li, C.; Chan, J.F.-W.; Cheng, Z.-S.; Yang, D.; Wang, D.; Lee, A.C.-Y.; Li, C.; et al. Middle East Respiratory Syndrome Coronavirus Efficiently Infects Human Primary T Lymphocytes and Activates the Extrinsic and Intrinsic Apoptosis Pathways. J. Infect. Dis. 2015, 213, 904–914.
  56. Fan, Y.-Y.; Huang, Z.-T.; Li, L.; Wu, M.-H.; Yu, T.; Koup, R.A.; Bailer, R.T.; Wu, C.-Y. Characterization of SARS-CoV-specific memory T cells from recovered individuals 4 years after infection. Arch. Virol. 2009, 154, 1093–1099.
  57. Li, C.K.-F.; Wu, H.; Yan, H.; Ma, S.; Wang, L.; Zhang, M.; Tang, X.; Temperton, N.; Weiss, R.A.; Brenchley, J.M.; et al. T Cell Responses to Whole SARS Coronavirus in Humans. J. Immunol. 2008, 181, 5490–5500.
  58. Xu, Z.; Shi, L.; Wang, Y.; Zhang, J.; Huang, L.; Zhang, C.; Liu, S.; Zhao, P.; Liu, H.; Zhu, L.; et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 2020, 8, 420–422.
  59. Wu, C.; Chen, X.; Cai, Y.; Xia, J.; Zhou, X.; Xu, S.; Huang, H.; Zhang, L.; Zhou, X.; Du, C.; et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. 2020, 180, 934–943.
  60. Diao, B.; Wang, C.; Tan, Y.; Chen, X.; Liu, Y.; Ning, L.; Chen, L.; Li, M.; Liu, Y.; Wang, G.; et al. Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease 2019 (COVID-19). Front. Immunol. 2020, 11, 827.
  61. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus—Infected Pneumonia in Wuhan, China. JAMA 2020, 323, 1061–1069.
  62. Zhang, W.; Zhao, Y.; Zhang, F.; Wang, Q.; Li, T.; Liu, Z.; Wang, J.; Qin, Y.; Zhang, X.; Yan, X.; et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin. Immunol. 2020, 214, 108393.
  63. Bai, Y.; Yao, L.; Wei, T.; Tian, F.; Jin, D.Y.; Chen, L.; Wang, M. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA 2020, 323, 1406–1407.
  64. Lau, S.K.P.; Lau, C.C.Y.; Chan, K.-H.; Li, C.P.Y.; Chen, H.; Jin, D.-Y.; Chan, J.F.W.; Woo, P.C.Y.; Yuen, K.-Y. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: Implications for pathogenesis and treatment. J. Gen. Virol. 2013, 94, 2679–2690.
  65. Yen, Y.-T.; Liao, F.; Hsiao, C.-H.; Kao, C.-L.; Chen, Y.-C.; Wu-Hsieh, B.A. Modeling the Early Events of Severe Acute Respiratory Syndrome Coronavirus Infection In Vitro. J. Virol. 2006, 80, 2684–2693.
  66. Pandey, M.K.; Rani, R.; Zhang, W.; Setchell, K.; Grabowski, G.A. Immunological cell type characterization and Th1–Th17 cytokine production in a mouse model of Gaucher disease. Mol. Genet. Metab. 2012, 106, 310–322.
  67. Pandey, M.K.; Grabowski, G.A. Immunological Cells and Functions in Gaucher Disease. Crit. Rev. Oncog. 2013, 18, 197–220.
  68. Gigis, I.; Pitsilos, C.; Samoladas, E.; Pavlopoulos, C.; Hytiroglou, P.; Ditsios, K.; Papadopoulos, P. Gaucher Disease: An Unusual Cause of Knee Pain. JAAOS Glob. Res. Rev. 2022, 6, 1–7.
  69. Rosenbloom, B.E.; Weinreb, N.J. Gaucher Disease: A Comprehensive Review. Crit. Rev. Oncog. 2013, 18, 163–175.
  70. Dandana, A.; Khelifa, B.S.; Chahed, H.; Miled, A.; Ferchichi, S. Gaucher Disease: Clinical, Biological and Therapeutic Aspects. Pathobiology 2016, 83, 13–23.
  71. Carubbi, F.; Cappellini, M.D.; Fargion, S.; Fracanzani, A.L.; Nascimbeni, F. Liver involvement in Gaucher disease: A practical review for the hepatologist and the gastroenterologist. Dig. Liv. Dis. 2020, 52, 368–373.
  72. Arévalo, N.B.; Lamaizon, C.M.; Cavieres, V.A.; Burgos, P.V.; Álvarez, A.R.; Yañez, M.J.; Zanlungo, S. Neuronopathic Gaucher disease: Beyond lysosomal dysfunction. Front. Mol. Neurosci. 2022, 15, 934820.
  73. Stirnemann, J.; Belmatoug, N.; Camou, F.; Serratrice, C.; Froissart, R.; Caillaud, C.; Levade, T.; Astudillo, L.; Serratrice, J.; Brassier, A.; et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int. J. Mol. Sci. 2017, 18, 441.
  74. Motta, I.; Splenomegaly Gaucher Group; Consonni, D.; Stroppiano, M.; Benedetto, C.; Cassinerio, E.; Tappino, B.; Ranalli, P.; Borin, L.; Facchini, L.; et al. Predicting the probability of Gaucher disease in subjects with splenomegaly and thrombocytopenia. Sci. Rep. 2021, 11, 2594.
  75. Lee, F.-S.; Yen, H.-J.; Niu, D.-M.; Hung, G.-Y.; Lee, C.-Y.; Yeh, Y.-C.; Chen, P.C.-H.; Chang, S.-K.; Yang, C.-F. Allogeneic hematopoietic stem cell transplantation for treating severe lung involvement in Gaucher disease. Mol. Genet. Metab. Rep. 2020, 25, 100652.
  76. Mauhin, W.; Brassier, A.; London, J.; Subran, B.; Zeggane, A.; Besset, Q.; Jammal, C.; Montardi, C.; Mellot, C.; Strauss, C.; et al. Manifestations pulmonaires des maladies héréditaires du métabolisme. Rev. Mal. Respir. 2022, 39, 758–777.
  77. ElFiky, A.A.; Mahdy, S.M.; Elshemey, W.M. Quantitative structure-activity relationship and molecular docking revealed a potency of anti-hepatitis C virus drugs against human corona viruses. J. Med. Virol. 2017, 89, 1040–1047.
  78. Chan, J.F.; Lau, S.K.; To, K.K.; Cheng, V.C.; Woo, P.C.; Yuen, K.Y. Middle East Respiratory Syndrome Coronavirus: Another Zoonotic Betacoronavirus Causing SARS-Like Disease. Clin. Microbiol. Rev. 2015, 28, 465–522.
  79. Cui, J.; Li, F.; Shi, Z.-L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 2019, 17, 181–192.
  80. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733.
  81. Fehr, A.R.; Perlman, S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol. Biol. 2015, 1282, 1–23.
  82. Boehm, M.; Nabel, E.G. Angiotensin-Converting Enzyme 2—A New Cardiac Regulator. N. Engl. J. Med. 2002, 347, 1795–1797.
  83. Crackower, M.A.; Sarao, R.; Oudit, G.Y.; Yagil, C.; Kozieradzki, I.; Scanga, S.E.; Oliveira-Dos-Santos, A.J.; Costa, D.J.; Zhang, L.; Pei, Y.; et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002, 417, 822–828.
  84. Marinho, P.M.; Marcos, A.A.A.; Romano, A.C.; Nascimento, H.; Belfort, R. Retinal findings in patients with COVID-19. Lancet 2020, 395, 1610.
  85. Zhou, P.; Yang, X.-L.; Wang, X.-G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.-R.; Zhu, Y.; Li, B.; Huang, C.-L.; et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020, 579, 270–273.
  86. Chen, J.; Jiang, Q.; Xia, X.; Liu, K.; Yu, Z.; Tao, W.; Gong, W.; Han, J.J. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 2020, 19, e13168.
  87. Seah, I.; Agrawal, R. Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals. Ocul. Immunol. Inflamm. 2020, 28, 391–395.
  88. Cardona, G.C.; Pájaro, L.D.Q.; Marzola, I.D.Q.; Villegas, Y.R.; Salazar, L.R.M. Neurotropism of SARS-CoV 2: Mechanisms and manifestations. J. Neurol. Sci. 2020, 412, 116824.
  89. Lu, C.-W.; Liu, X.-F.; Jia, Z.-F. 2019-nCoV transmission through the ocular surface must not be ignored. Lancet 2020, 395, e39.
  90. Seah, I.; Su, X.; Lingam, G. Revisiting the dangers of the coronavirus in the ophthalmology practice. Eye 2020, 34, 1155–1157.
  91. Cheema, M.; Aghazadeh, H.; Nazarali, S.; Ting, A.; Hodges, J.; McFarlane, A.; Kanji, J.N.; Zelyas, N.; Damji, K.F.; Solarte, C. Keratoconjunctivitis as the initial medical presentation of the novel coronavirus disease 2019 (COVID-19). Can. J. Ophthalmol. 2020, 55, e125–e129.
  92. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e278.
  93. Liu, C.; Zhou, Q.; Li, Y.; Garner, L.V.; Watkins, S.P.; Carter, L.J.; Smoot, J.; Gregg, A.C.; Daniels, A.D.; Jervey, S.; et al. Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases. ACS Cent. Sci. 2020, 6, 315–331.
  94. Mokhtari, T.; Hassani, F.; Ghaffari, N.; Ebrahimi, B.; Yarahmadi, A.; Hassanzadeh, G. COVID-19 and multiorgan failure: A narrative review on potential mechanisms. Histochem. J. 2020, 51, 613–628.
  95. Guan, W.J.; Ni, Z.Y.; Hu, Y.; Liang, W.H.; Qu, C.Q.; He, J.X.; Liu, L.; Shan, H.; Lei, C.L.; Hui, D.S.C.; et al. Clinical Characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 2020, 382, 1708–1720.
  96. Camporota, L.; Cronin, J.N.; Busana, M.; Gattinoni, L.; Formenti, F. Pathophysiology of coronavirus-19 disease acute lung injury. Curr. Opin. Crit. Care. 2022, 28, 9–16.
  97. Wan, S.; Yi, Q.; Fan, S.; Lv, J.; Zhang, X.; Guo, L.; Lang, C.; Xiao, Q.; Xiao, K.; Yi, Z.; et al. Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients. Br. J. Haematol. 2020, 189, 428–437.
  98. Zawawi, A.; Naser, A.Y.; Alwafi, H.; Minshawi, F. Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis. Front. Immunol. 2021, 12, 666223.
  99. Chien, J.-Y.; Hsueh, P.-R.; Cheng, W.-C.; Yu, C.-J.; Yang, P.-C. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology 2006, 11, 715–722.
  100. Wang, C.-H.; Liu, C.-Y.; Wan, Y.-L.; Chou, C.-L.; Huang, K.-H.; Lin, H.-C.; Lin, S.-M.; Lin, T.-Y.; Chung, K.F.; Kuo-Hsiung, H. Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS. Respir. Res. 2005, 6, 42.
  101. Wong, C.K.; Lam, C.W.K.; Wu, A.K.L.; Ip, W.K.; Lee, N.L.S.; Chan, I.H.S.; Lit, L.C.W.; Hui, D.S.C.; Chan, M.H.M.; Chung, S.S.C.; et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 2004, 136, 95–103.
  102. Zhang, Y.; Li, J.; Zhan, Y.; Wu, L.; Yu, X.; Zhang, W.; Ye, L.; Xu, S.; Sun, R.; Wang, Y.; et al. Analysis of Serum Cytokines in Patients with Severe Acute Respiratory Syndrome. Infect. Immun. 2004, 72, 4410–4415.
  103. Cameron, M.J.; Bermejo-Martin, J.F.; Danesh, A.; Muller, M.P.; Kelvin, D.J. Human immunopathogenesis of severe acute respiratory syndrome (SARS). Virus Res. 2008, 133, 13–19.
  104. Cameron, M.J.; Ran, L.; Xu, L.; Danesh, A.; Bermejo-Martin, J.F.; Cameron, C.M.; Muller, M.P.; Gold, W.L.; Richardson, S.E.; Poutanen, S.M.; et al. Interferon-Mediated Immunopathological Events Are Associated with Atypical Innate and Adaptive Immune Responses in Patients with Severe Acute Respiratory Syndrome. J. Virol. 2007, 81, 8692–8706.
  105. Huang, K.-J.; Su, I.-J.; Theron, M.; Wu, Y.-C.; Lai, S.-K.; Liu, C.-C.; Lei, H.-Y. An interferon-?-related cytokine storm in SARS patients. J. Med. Virol. 2004, 75, 185–194.
  106. Theron, M.; Huang, K.-J.; Chen, Y.-W.; Liu, C.-C.; Lei, H.-Y. A probable role for IFN-γ in the development of a lung immunopathology in SARS. Cytokine 2005, 32, 30–38.
  107. Kim, J.S.; Lee, J.Y.; Yang, J.W.; Lee, K.H.; Effenberger, M.; Szpirt, W.; Kronbichler, A.; Shin, J.I. Immunopathogenesis and treatment of cytokine storm in COVID-19. Theranostics 2021, 11, 316–329.
  108. Channappanavar, R.; Perlman, S. Pathogenic human coronavirus infections: Causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 2017, 39, 529–539.
  109. Chen, Y.; Wang, J.; Liu, C.; Su, L.; Zhang, D.; Fan, J.; Yang, Y.; Xiao, M.; Xie, J.; Xu, Y.; et al. IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19. Mol. Med. 2020, 26, 97.
  110. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506.
  111. Conti, P.; Gallenga, C.E.; Tete, G.; Caraffa, A.; Ronconi, G.; Younes, A.; Toniato, E.; Ross, R.; Kritas, S.K. How to reduce the likelihood of coronavirus-19 (CoV-19 or SARS-CoV-2) infection and lung inflammation mediated by IL-1. J. Biol. Regul. Homeost. Agents 2020, 34, 333–338.
  112. Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020, 46, 846–848.
  113. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513.
  114. McElvaney, O.J.; McEvoy, N.L.; McElvaney, O.F.; Carroll, T.P.; Murphy, M.P.; Dunlea, D.M.; Choileain, N.O.; Clarke, J.; O’Connor, E.; Hogan, G.; et al. Characterization of the Inflammatory Response to Severe COVID-19 Illness. Am. J. Respir. Crit. Care Med. 2020, 202, 812–821.
  115. Pandey, M.K.; Jabre, N.A.; Xu, Y.-H.; Zhang, W.; Setchell, K.D.; Grabowski, G.A. Gaucher disease: Chemotactic factors and immunological cell invasion in a mouse model. Mol. Genet. Metab. 2014, 111, 163–171.
  116. Zahran, A.M.; Saad, K.; Abdallah, A.-E.M.; Gad, E.F.; Abdel-Raheem, Y.F.; Zahran, Z.A.M.; Abdelsalam, E.M.N.; Elhoufey, A.; Alruwaili, T.; Mahmoud, K.H.; et al. Dendritic cells and monocyte subsets in children with Gaucher disease. Pediatr. Res. 2021, 90, 664–669.
  117. Micheva, I.; Marinakis, T.; Repa, C.; Kouraklis-Symeonidis, A.; Vlacha, V.; Anagnostopoulos, N.; Zoumbos, N. Dendritic cells in patients with type I Gaucher disease are decreased in number but functionally normal. Blood Cells Mol. Dis. 2006, 36, 298–307.
  118. Magnusen, A.F.; Rani, R.; McKay, M.A.; Hatton, S.L.; Nyamajenjere, T.C.; Magnusen, D.N.A.; Köhl, J.; Grabowski, G.A.; Pandey, M.K. C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease. Int. J. Mol. Sci. 2021, 22, 12712.
  119. Mistry, P.K.; Liu, J.; Yang, M.; Nottoli, T.; McGrath, J.; Jain, D.; Zhang, K.; Keutzer, J.; Chuang, W.-L.; Mehal, W.Z.; et al. Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. Proc. Natl. Acad. Sci. USA 2010, 107, 19473–19478.
  120. Kim, N.E.; Do, H.; Jeong, H.; Kim, T.; Heo, S.H.; Kim, Y.; Cheon, C.K.; Lee, Y.; Choi, Y.; Choi, I.H.; et al. Identification of a novel therapeutic target underlying atypical manifestation of Gaucher disease. Clin. Transl. Med. 2022, 12, e862.
  121. Braudeau, C.; Graveleau, J.; Rimbert, M.; Néel, A.; Hamidou, M.; Grosbois, B.; Besançon, A.; Giraudet, S.; Terrien, C.; Josien, R.; et al. Altered innate function of plasmacytoid dendritic cells restored by enzyme replacement therapy in Gaucher disease. Blood Cells Mol. Dis. 2013, 50, 281–288.
  122. Sønder, S.U.; Limgala, R.P.; Ivanova, M.M.; Ioanou, C.; Plassmeyer, M.; Marti, G.E.; Alpan, O.; Goker-Alpan, O. Persistent immune alterations and comorbidities in splenectomized patients with Gaucher disease. Blood Cells Mol. Dis. 2016, 59, 8–15.
  123. Zahran, A.M.; Saad, K.; Elsayh, K.I.; Abdou, M.A.A.; Abo-Elgheet, A.M.; Eloseily, E.M.; Khalaf, S.M.; Sror, S.; Ahmad, F.-A.; Elhoufey, A.; et al. Upregulation of Cytotoxic T-cells in pediatric patients with Gaucher disease. Sci. Rep. 2022, 12, 4977.
  124. Nguyen, Y.; Stirnemann, J.; Belmatoug, N. La maladie de Gaucher: Quand y penser? Revue Méd. Interne 2019, 40, 313–322.
  125. Grabowski, G.A.; Antommaria, A.H.; Kolodny, E.H.; Mistry, P.K. Gaucher disease: Basic and translational science needs for more complete therapy and management. Mol. Genet. Metab. 2020, 132, 59–75.
  126. Grabowski, G.A.; Mistry, P.K. Therapies for lysosomal storage diseases: Principles, practice, and prospects for refinements based on evolving science. Mol. Genet. Metab. 2022, 137, 81–91.
  127. Xu, Y.H.; Quinn, B.; Witte, D.; Grabowski, G.A. Viable mouse models of acid beta-glucosidase deficiency: The defect in Gaucher disease. Am. J. Pathol. 2003, 163, 2093–2101.
  128. Pandey, M.K.; Grabowski, G.A. Advances in Gaucher Disease: Basic and Clinical Perspectives 78–93; Future Medicine Ltd.: London, UK, 2013.
  129. Koprivica, V.; Stone, D.L.; Park, J.K.; Callahan, M.; Frisch, A.; Cohen, I.J.; Tayebi, N.; Sidransky, E. Analysis and Classification of 304 Mutant Alleles in Patients with Type 1 and Type 3 Gaucher Disease. Am. J. Hum. Genet. 2000, 66, 1777–1786.
  130. Sun, Y.; Liou, B.; Ran, H.; Skelton, M.R.; Williams, M.T.; Vorhees, C.V.; Kitatani, K.; Hannun, Y.A.; Witte, D.P.; Xu, Y.-H.; et al. Neuronopathic Gaucher disease in the mouse: Viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Hum. Mol. Genet. 2010, 19, 1088–1097.
  131. Wong, K.; Sidransky, E.; Verma, A.; Mixon, T.; Sandberg, G.D.; Wakefield, L.K.; Morrison, A.; Lwin, A.; Colegial, C.; Allman, J.M.; et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol. Genet. Metab. 2004, 82, 192–207.
  132. Vitner, E.B.; Farfel-Becker, T.; Eilam, R.; Biton, I.; Futerman, A. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain 2012, 135, 1724–1735.
  133. Vitner, E.B.; Dekel, H.; Zigdon, H.; Shachar, T.; Farfel-Becker, T.; Eilam, R.; Karlsson, S.; Futerman, A.H. Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum. Mol. Genet. 2010, 19, 3583–3590.
  134. Dasgupta, N.; Xu, Y.-H.; Li, R.; Peng, Y.; Pandey, M.K.; Tinch, S.L.; Liou, B.; Inskeep, V.; Zhang, W.; Setchell, K.D.; et al. Neuronopathic Gaucher disease: Dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model. Hum. Mol. Genet. 2015, 24, 7031–7048.
  135. Orvisky, E.; Park, J.; Parker, A.; Walker, J.; Martin, B.; Stubblefield, B.; Uyama, E.; Tayebi, N.; Sidransky, E. The identification of eight novel glucocerebrosidase (GBA) mutations in patients with Gaucher disease. Hum. Mutat. 2002, 19, 458–459.
  136. Conradi, N.G.; Sourander, P.; Nilsson, O.; Svennerholm, L.; Erikson, A. Neuropathology of the Norrbottnian type of Gaucher disease. Acta Neuropathol. 1984, 65, 99–109.
  137. Gegg, M.E.; Burke, D.; Heales, S.J.R.; Cooper, J.M.; Hardy, J.; Wood, N.W.; Schapira, A.H.V. Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains. Ann. Neurol. 2012, 72, 455–463.
  138. Murphy, K.E.; Gysbers, A.M.; Abbott, S.K.; Tayebi, N.; Kim, W.S.; Sidransky, E.; Cooper, A.; Garner, B.; Halliday, G.M. Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease. Brain 2014, 137 Pt 3, 834–848.
  139. Farfel-Becker, T.; Vitner, E.B.; Kelly, S.L.; Bame, J.R.; Duan, J.; Shinder, V.; Merrill, A.H., Jr.; Dobrenis, K.; Futerman, A.H. Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Hum. Mol. Genet. 2013, 23, 843–854.
  140. Mignot, C.; Doummar, D.; Maire, I.; Villemeur, D.T.B. Type 2 Gaucher disease: 15 new cases and review of the literature. Brain Dev. 2006, 28, 39–48.
  141. Gupta, N.; Oppenheim, I.; Kauvar, E.; Tayebi, N.; Sidransky, E. Type 2 Gaucher disease: Phenotypic variation and genotypic heterogeneity. Blood Cells Mol. Dis. 2011, 46, 75–84.
  142. Harris, C.; Taylor, D.; Vellodi, A. Ocular Motor Abnormalities in Gaucher Disease. Neuropediatrics 1999, 30, 289–293.
  143. Cogan, D.G.; Chu, F.C.; Reingold, D.; Barranger, J. Ocular Motor Signs in Some Metabolic Diseases. Arch. Ophthalmol. 1981, 99, 1802–1808.
  144. Sidransky, E.; Tsujl, S.; Stubblefield, B.K.; Gurrie, J.; FitzGibbon, E.J.; Glnns, E.I. Gaudier patients with oculomotor abnormalities do not have a unique genotype. Clin. Genet. 2008, 41, 1–5.
  145. Patterson, M.C.; Horowitz, M.; Abel, R.B.; Currie, J.N.; Yu, K.-T.; Kaneski, C.; Higgins, J.J.; O’Neill, R.R.; Fedio, P.; Pikus, A.; et al. Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher’s disease. Neurology 1993, 43, 1993.
  146. King, J.O. Progressive myoclonic epilepsy due to Gaucher’s disease in an adult. J. Neurol. Neurosurg. Psychiatry 1975, 38, 849–854.
  147. Winkelman, M.D.; Banker, B.Q.; Victor, M.; Moser, H.W. Non-infantile neuronopathic Gaucher’s disease: A clinicopathologic study. Neurology 1983, 33, 994.
  148. Neil, J.F.; Glew, R.H.; Peters, S.P. Familial Psychosis and Diverse Neurologic Abnormalities in Adult-Onset Gaucher’s Disease. Arch. Neurol. 1979, 36, 95–99.
  149. Yoshikawa, H.; Fueki, N.; Sasaki, M.; Sakuragawa, N. Uncoupling of blood flow and oxygen metabolism in the cerebellum in type 3 Gaucher disease. Brain Dev. 1991, 13, 190–192.
  150. Seeman, P.; Hoppner, J.; Lakner, V.; Liebisch, I.; Grau, G.; Rolfs, A.; Finckh, U. Two new missense mutations in a non-Jewish Caucasian family with type 3 Gaucher disease. Neurology 1996, 46, 1102–1107.
  151. Grover, W.D.; Tucker, S.H.; Wenger, D.A. Clinical variation in 2 related children with neuronopathic Gaucher disease. Ann. Neurol. 1978, 3, 281–283.
  152. Conradi, N.; Kyllerman, M.; Percy, A.K.; Svennerholm, L. Late-infantile Gaucher disease in a child with myoclonus and bulbar signs: Neuropathological and neurochemical findings. Acta Neuropathol. 1991, 82, 152–157.
  153. Dobbelaere, D.; Sukno, S.; Defoort-Dhellemmes, S.; Lamblin, M.-D.; Largillière, C. Neurological outcome of a patient with Gaucher disease type III treated by enzymatic replacement therapy. J. Inherit. Metab. Dis. 1998, 21, 74–76.
  154. Verghese, J.; Goldberg, R.F.; Desnick, R.J.; Grace, M.E.; Goldman, J.E.; Lee, S.C.; Dickson, D.W.; Rapin, I. Myoclonus from selective dentate nucleus degeneration in type 3 Gaucher disease. Arch. Neurol. 2000, 57, 389–395.
  155. Erikson, A. Gaucher disease-Norrbottnian type (III). Acta Paediatr. 1986, 75, 1–42.
  156. Park, J.K.; Orvisky, E.; Tayebi, N.; Kaneski, C.; Lamarca, M.E.; Stubblefield, B.K.; Martin, B.M.; Schiffmann, R.; Sidransky, E. Myoclonic Epilepsy in Gaucher Disease: Genotype-Phenotype Insights from a Rare Patient Subgroup. Pediatr. Res. 2003, 53, 387–395.
  157. Limgala, R.P.; Ioanou, C.; Plassmeyer, M.; Ryherd, M.; Kozhaya, L.; Austin, L.; Abidoglu, C.; Unutmaz, D.; Alpan, O.; Goker-Alpan, O. Time of Initiating Enzyme Replacement Therapy Affects Immune Abnormalities and Disease Severity in Patients with Gaucher Disease. PLoS ONE 2016, 11, e0168135.
  158. Zahran, A.M.; Youssef, M.A.M.; Shafik, E.A.; Zahran, Z.A.M.; El-Badawy, O.; Elgheet, A.M.A.; Elsayh, K.I. Downregulation of B regulatory cells and upregulation of T helper 1 cells in children with Gaucher disease undergoing enzyme replacement therapy. Immunol. Res. 2020, 68, 73–80.
  159. Kishnani, P.S.; Dickson, P.I.; Muldowney, L.; Lee, J.J.; Rosenberg, A.; Abichandani, R.; Bluestone, J.A.; Burton, B.K.; Dewey, M.; Freitas, A.; et al. Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction. Mol. Genet. Metab. 2016, 117, 66–83.
  160. Mistry, P.K.; Lopez, G.; Schiffmann, R.; Barton, N.W.; Weinreb, N.J.; Sidransky, E. Gaucher disease: Progress and ongoing challenges. Mol. Genet. Metab. 2017, 120, 8–21.
  161. Ohashi, T. Molecular diagnosis and gene therapy for Gaucher disease. Nihon Rinsho Jpn. J. Clin. Med. 1993, 51, 2300–2307.
  162. Bennett, L.L.; Fellner, C. Pharmacotherapy of Gaucher Disease: Current and Future Options. PTA Peer Rev. J. Formul. Manag. 2018, 43, 274–309.
  163. Silva, A.K.A.; Sagné, C.; Gazeau, F.; Abasolo, I. Enzyme replacement therapy: Current challenges and drug delivery prospects via extracellular vesicles. Rare Dis. Orphan Drugs J. 2022, 1, 13.
  164. Veerhuis, R.; Nielsen, H.M.; Tenner, A.J. Complement in the brain. Mol. Immunol. 2011, 48, 1592–1603.
  165. Bajic, G.; Degn, S.E.; Thiel, S.; Andersen, G.R. Complement activation, regulation, and molecular basis for complement-related diseases. EMBO J. 2015, 34, 2735–2757.
  166. Magdalon, J.; Mansur, F.; Silva, A.L.T.E.; Goes, D.V.A.; Reiner, O.; Sertié, A.L. Complement System in Brain Architecture and Neurodevelopmental Disorders. Front. Neurosci. 2020, 14, 23.
  167. Ricklin, D.; Hajishengallis, G.; Yang, K.; Lambris, J.D. Complement: A key system for immune surveillance and homeostasis. Nat. Immunol. 2010, 11, 785–797.
  168. Yan, C.; Gao, H. New insights for C5a and C5a receptors in sepsis. Front. Immunol. 2012, 3, 368.
  169. Law, S.K.; Levine, R.P. Interaction between the third complement protein and cell surface macromolecules. Proc. Natl. Acad. Sci. USA 1977, 74, 2701–2705.
  170. Hein, E.; Garred, P. Immune Responses to Biosurfaces; Lambris, J.D., Ekdahl, K.N., Ricklin, D., Nilsson, B., Eds.; Springer International Publishing: Cham, Switzerland, 2015; pp. 77–92.
  171. Sørensen, R.; Thiel, S.; Jensenius, J.C. Mannan-binding-lectin-associated serine proteases, characteristics and disease associations. Springer Semin. Immunopathol. 2005, 27, 299–319.
  172. Schartz, N.D.; Tenner, A.J. The good, the bad, and the opportunities of the complement system in neurodegenerative disease. J. Neuroinflamm. 2020, 17, 354.
  173. Morgan, B.P.; Harris, C.L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 2015, 14, 857–877.
  174. Orsini, F.; Blasio, D.D.; Zangari, R.; Zanier, E.R.; de Simoni, M.G.; Orsini, F.; Blasio, D.D.; Zangari, R.; Zanier, E.R.; de Simoni, M.G. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front. Cell Neurosci. 2014, 8, 380.
  175. Kolev, M.; Friec, L.G.; Kemper, C. Complement—Tapping into new sites and effector systems. Nat. Rev. Immunol. 2014, 14, 811–820.
  176. Cedzyński, M.; Thielens, N.M.; Mollnes, T.E.; Vorup-Jensen, T. Editorial: The Role of Complement in Health and Disease. Front. Immunol. 2019, 10, 1869.
  177. Stevens, B.; Allen, N.J.; Vazquez, L.E.; Howell, G.R.; Christopherson, K.S.; Nouri, N.; Micheva, K.D.; Mehalow, A.K.; Huberman, A.D.; Stafford, B.; et al. The Classical Complement Cascade Mediates CNS Synapse Elimination. Cell 2007, 131, 1164–1178.
  178. Schafer, D.P.; Lehrman, E.K.; Kautzman, A.G.; Koyama, R.; Mardinly, A.R.; Yamasaki, R.; Ransohoff, R.M.; Greenberg, M.E.; Barres, B.A.; Stevens, B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 2012, 74, 691–705.
  179. Hou, L.; Bao, X.; Zang, C.; Yang, H.; Sun, F.; Che, Y.; Wu, X.; Li, S.; Zhang, D.; Wang, Q. Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway. Redox Biol. 2017, 14, 600–608.
  180. Stephan, A.H.; Barres, B.A.; Stevens, B. The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease. Annu. Rev. Neurosci. 2012, 35, 369–389.
  181. Kaartinen, K.; Safa, A.; Kotha, S.; Ratti, G.; Meri, S. Complement dysregulation in glomerulonephritis. Semin. Immunol. 2019, 45, 101331.
  182. Köhl, J.; Baelder, R.; Lewkowich, I.P.; Pandey, M.K.; Hawlisch, H.; Wang, L.; Best, J.; Herman, N.S.; Sproles, A.A.; Zwirner, J.; et al. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J. Clin. Investig. 2006, 116, 783–796.
  183. Fritsche, L.G.; Lauer, N.; Hartmann, A.; Stippa, S.; Keilhauer, C.N.; Oppermann, M.; Pandey, M.K.; Köhl, J.; Zipfel, P.F.; Weber, B.H.; et al. An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). Hum. Mol. Genet. 2010, 19, 4694–4704.
  184. Mahajan, S.D.; Parikh, N.U.; Woodruff, T.M.; Jarvis, J.N.; Lopez, M.; Hennon, T.; Cunningham, P.; Quigg, R.J.; Schwartz, S.A.; Alexander, J.J. C5a alters blood-brain barrier integrity in a human in vitro model of systemic lupus erythematosus. Immunology 2015, 146, 130–143.
  185. Jacob, A.; Hack, B.; Chen, P.; Quigg, R.J.; Alexander, J.J. C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-κB. J. Neurochem. 2011, 119, 1041–1051.
  186. Jacob, A.; Hack, B.; Chiang, E.; Garcia, J.G.N.; Quigg, R.J.; Alexander, J.J. C5a alters blood-brain barrier integrity in experimental lupus. FASEB J. 2010, 24, 1682–1688.
  187. Flierl, M.A.; Stahel, P.F.; Rittirsch, D.; Huber-Lang, M.; Niederbichler, A.D.; Hoesel, L.M.; Touban, B.M.; Morgan, S.J.; Smith, W.R.; Ward, P.A.; et al. Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis. Crit. Care 2009, 13, R12.
  188. Landlinger, C.; Oberleitner, L.; Gruber, P.; Noiges, B.; Yatsyk, K.; Santic, R.; Mandler, M.; Staffler, G. Active immunization against complement factor C5a: A new therapeutic approach for Alzheimer’s disease. J. Neuroinflamm. 2015, 12, 150.
  189. Woodruff, T.M.; Crane, J.W.; Proctor, L.M.; Buller, K.M.; Shek, A.B.; Vos, D.K.; Pollitt, S.; Williams, H.M.; Shiels, I.A.; Monk, P.N.; et al. Therapeutic activity of C5a receptor antagonists in a rat model of neurodegeneration. FASEB J. 2006, 20, 1407–1417.
  190. Farkas, I.; Takahashi, M.; Fukuda, A.; Yamamoto, N.; Akatsu, H.; Baranyi, L.; Tateyama, H.; Yamamoto, T.; Okada, N.; Okada, H. Complement C5a Receptor-Mediated Signaling May Be Involved in Neurodegeneration in Alzheimer’s Disease. J. Immunol. 2003, 170, 5764–5771.
  191. Yuan, B.; Fu, F.; Huang, S.; Lin, C.; Yang, G.; Ma, K.; Shi, H.; Yang, Z. C5a/C5aR Pathway Plays a Vital Role in Brain Inflammatory Injury via Initiating Fgl-2 in Intracerebral Hemorrhage. Mol. Neurobiol. 2016, 54, 6187–6197.
  192. Kim, G.H.; Mocco, J.; Hahn, D.K.; Kellner, C.P.; Komotar, R.J.; Ducruet, A.F.; Mack, W.J.; Connolly, E.S. Protective Effect of C5a Receptor Inhibition after Murine Reperfused Stroke. Neurosurgery 2008, 63, 122–126.
  193. Lee, J.D.; Kumar, V.; Fung, J.N.T.; Ruitenberg, M.J.; Noakes, P.G.; Woodruff, T.M. Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. J. Cereb. Blood Flow Metab. 2017, 174, 689–699.
  194. Piatek, P.; Domowicz, M.; Lewkowicz, N.; Przygodzka, P.; Matysiak, M.; Dzitko, K.; Lewkowicz, P. C5a-Preactivated Neutrophils Are Critical for Autoimmune-Induced Astrocyte Dysregulation in Neuromyelitis Optica Spectrum Disorder. Front. Immunol. 2018, 9, 1694.
  195. McGeer, P.L.; McGeer, E.G. The possible role of complement activation in Alzheimer disease. Trends Mol. Med. 2002, 8, 519–523.
  196. Shen, Y.; Meri, S. Yin and Yang: Complement activation and regulation in Alzheimer’s disease. Prog. Neurobiol. 2003, 70, 463–472.
  197. Yamada, T.; McGeer, P.L.; McGeer, E.G. Lewy bodies in Parkinson’s disease are recognized by antibodies to complement proteins. Acta Neuropathol. 1992, 84, 100–104.
  198. Iseki, E.; Marui, W.; Akiyama, H.; Uéda, K.; Kosaka, K. Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using α-synuclein-immunohistochemistry. Neurosci. Lett. 2000, 286, 69–73.
  199. Tan, S.M.; Snelson, M.; Østergaard, J.A.; Coughlan, M.T. The Complement Pathway: New Insights into Immunometabolic Signaling in Diabetic Kidney Disease. Antioxid. Redox Signal 2022, 37, 781–801.
  200. O’Brien, K.B.; Morrison, T.E.; Dundore, D.Y.; Heise, M.T.; Schultz-Cherry, S. A Protective Role for Complement C3 Protein during Pandemic 2009 H1N1 and H5N1 Influenza A Virus Infection. PLoS ONE 2011, 6, e17377.
  201. Jiang, Y.; Zhao, G.; Song, N.; Li, P.; Chen, Y.; Guo, Y.; Li, J.; Du, L.; Jiang, S.; Guo, R.; et al. Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerg. Microbes Infect. 2018, 7, 77.
  202. Jiang, Y.; Li, J.; Teng, Y.; Sun, H.; Tian, G.; He, L.; Li, P.; Chen, Y.; Guo, Y.; Li, J.; et al. Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV. Viruses 2019, 11, 39.
  203. Posch, W.; Vosper, J.; Noureen, A.; Zaderer, V.; Witting, C.; Bertacchi, G.; Gstir, R.; Filipek, P.A.; Bonn, G.K.; Huber, L.A.; et al. C5aR inhibition of nonimmune cells suppresses inflammation and maintains epithelial integrity in SARS-CoV-2–infected primary human airway epithelia. J. Allergy Clin. Immunol. 2021, 147, 2083–2097.e6.
  204. Laurence, J.; Mulvey, J.J.; Seshadri, M.; Racanelli, A.; Harp, J.; Schenck, E.J.; Zappetti, D.; Horn, E.M.; Magro, C.M. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin. Immunol. 2020, 219, 108555.
  205. Lo, M.W.; Kemper, C.; Woodruff, T.M. COVID-19: Complement, Coagulation, and Collateral Damage. J. Immunol. 2020, 205, 1488–1495.
  206. Mastellos, D.C.; da Silva, B.G.P.; Fonseca, B.A.; Fonseca, N.P.; Auxiliadora-Martins, M.; Mastaglio, S.; Ruggeri, A.; Sironi, M.; Radermacher, P.; Chrysanthopoulou, A.; et al. Complement C3 vs. C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy. Clin. Immunol. 2020, 220, 108598.
  207. Conway, E.M.; Pryzdial, E.L.G. Is the COVID-19 thrombotic catastrophe complement-connected? J. Thromb. Haemost. 2020, 18, 2812–2822.
  208. Fletcher-Sandersjöö, A.; Bellander, B.-M. Is COVID-19 associated thrombosis caused by overactivation of the complement cascade? A literature review. Thromb. Res. 2020, 194, 36–41.
  209. Boussier, J.; Yatim, N.; Marchal, A.; Hadjadj, J.; Charbit, B.; Sissy, E.C.; Carlier, N.; Pène, F.; Mouthon, L.; Tharaux, P.-L.; et al. Severe COVID-19 is associated with hyperactivation of the alternative complement pathway. J. Allergy Clin. Immunol. 2022, 149, 550–556.e2.
  210. Santiesteban-Lores, L.E.; Amamura, T.A.; da Silva, T.F.; Midon, L.M.; Carneiro, M.C.; Isaac, L.; Bavia, L. A double edged-sword-The Complement System during SARS-CoV-2 infection. Life Sci. 2021, 272, 119245.
  211. Droesch, C.; Do, M.H.; DeSancho, M.; Lee, E.-J.; Magro, C.; Harp, J. Livedoid and Purpuric Skin Eruptions Associated With Coagulopathy in Severe COVID-19. JAMA Dermatol. 2020, 156, 1022.
  212. Yu, J.; Gerber, G.F.; Chen, H.; Yuan, X.; Chaturvedi, S.; Braunstein, E.M.; Brodsky, R.A. Complement dysregulation is associated with severe COVID-19 illness. Haematologica 2021, 107, 1095–1105.
  213. Yu, J.; Yuan, X.; Chen, H.; Chaturvedi, S.; Braunstein, E.M.; Brodsky, R.A. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. Blood 2020, 136, 2080–2089.
  214. Satyam, A.; Tsokos, M.G.; Brook, O.R.; Hecht, J.L.; Moulton, V.R.; Tsokos, G.C. Activation of classical and alternative complement pathways in the pathogenesis of lung injury in COVID-19. Clin. Immunol. 2021, 226, 108716.
  215. Pandey, M.K. The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans. Front. Aging Neurosci. 2022, 14, 1–16.
  216. Nimmerjahn, F.; Ravetch, J.V. Fcγ Receptors: Old Friends and New Family Members. Immunity 2006, 24, 19–28.
  217. Liu, L.; Wang, P.; Nair, M.S.; Yu, J.; Rapp, M.; Wang, Q.; Luo, Y.; Chan, J.F.; Sahi, V.; Figueroa, A.; et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature 2020, 584, 450–456.
  218. Gaebler, C.; Wang, Z.; Lorenzi, J.C.C.; Muecksch, F.; Finkin, S.; Tokuyama, M.; Cho, A.; Jankovic, M.; Schaefer-Babajew, D.; Oliveira, T.Y.; et al. Evolution of antibody immunity to SARS-CoV-2. Nature 2021, 591, 639–644.
  219. Turner, J.S.; Kim, W.; Kalaidina, E.; Goss, C.W.; Rauseo, A.M.; Schmitz, A.J.; Hansen, L.; Haile, A.; Klebert, M.K.; Pusic, I.; et al. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature 2021, 595, 421–425.
  220. Nguyen-Contant, P.; Embong, A.K.; Kanagaiah, P.; Chaves, F.A.; Yang, H.; Branche, A.R.; Topham, D.J.; Sangster, M.Y. S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit. mBio 2020, 11, e01991-20.
  221. Hartley, G.E.; Edwards, E.S.J.; Aui, P.M.; Varese, N.; Stojanovic, S.; McMahon, J.; Peleg, A.Y.; Boo, I.; Drummer, H.E.; Hogarth, P.M.; et al. Rapid Generation of Durable B Cell Memory to SARS-CoV-2 Spike and Nucleocapsid Proteins in COVID-19 and Convalescence. Sci. Immunol. 2020, 5, eabf8891.
  222. Williams, J.W.; Tjota, M.Y.; Sperling, A.I. The Contribution of Allergen-Specific IgG to the Development of Th2-Mediated Airway Inflammation. J. Allergy 2012, 2012, 236075.
  223. Karsten, C.M.; Köhl, J. The immunoglobulin, IgG Fc receptor and complement triangle in autoimmune diseases. Immunobiology 2012, 217, 1067–1079.
  224. Nimmerjahn, F.; Bruhns, P.; Horiuchi, K.; Ravetch, J.V. FcγRIV: A Novel FcR with Distinct IgG Subclass Specificity. Immunity 2005, 23, 41–51.
  225. Seino, J.; Eveleigh, P.; Warnaar, S.; van Haarlem, L.J.M.; van Es, L.A.; Daha, M.R. Activation of human complement by mouse and mouse/human chimeric monoclonal antibodies. Clin. Exp. Immunol. 1993, 94, 291–296.
  226. Syed, S.N.; Konrad, S.; Wiege, K.; Nieswandt, B.; Nimmerjahn, F.; Schmidt, R.E.; Gessner, J.E. Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ-LAT-dependent generation of C5a. Eur. J. Immunol. 2009, 39, 3343–3356.
  227. Pandey, M.K. Molecular Basis for Downregulation of C5a-Mediated Inflammation by IgG1 Immune Complexes in Allergy and Asthma. Curr. Allergy Asthma Rep. 2013, 13, 596–606.
  228. Pandey, M.K.; Burrow, T.A.; Rani, R.; Martin, L.J.; Witte, D.; Setchell, K.D.; Mckay, M.A.; Magnusen, A.F.; Zhang, W.; Liou, B.; et al. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature 2017, 543, 108–112.
  229. Schäfer, A.; Muecksch, F.; Lorenzi, J.C.; Leist, S.R.; Cipolla, M.; Bournazos, S.; Schmidt, F.; Maison, R.M.; Gazumyan, A.; Martinez, D.R.; et al. Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo. J. Exp. Med. 2020, 218, 1–14.
  230. Moncunill, G.; Mayor, A.; Santano, R.; Jiménez, A.; Vidal, M.; Tortajada, M.; Sanz, S.; Méndez, S.; Llupià, A.; Aguilar, R.; et al. SARS-CoV-2 Seroprevalence and Antibody Kinetics Among Health Care Workers in a Spanish Hospital After 3 Months of Follow-up. J. Infect. Dis. 2020, 223, 62–71.
  231. Serfecz, J.C.; Saadin, A.; Santiago, C.P.; Zhang, Y.; Bentzen, S.M.; Vogel, S.N.; Feldman, R.A. C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages. Int. J. Mol. Sci. 2021, 22, 9912.
  232. Dasgupta, N.; Xu, Y.-H.; Oh, S.; Sun, Y.; Jia, L.; Keddache, M.; Grabowski, G.A. Gaucher Disease: Transcriptome Analyses Using Microarray or mRNA Sequencing in a Gba1 Mutant Mouse Model Treated with Velaglucerase alfa or Imiglucerase. PLoS ONE 2013, 8, e74912.
  233. Xu, Y.-H.; Jia, L.; Quinn, B.; Zamzow, M.; Stringer, K.; Aronow, B.; Sun, Y.; Zhang, W.; Setchell, K.; Grabowski, G.A. Global gene expression profile progression in Gaucher disease mouse models. BMC Genom. 2011, 12, 20.
  234. Guo, R.-F.; Ward, P.A. Role of C5a in Inflammatory Responses. Annu. Rev. Immunol. 2005, 23, 821–852.
  235. Zhang, X.; Köhl, J. A complex role for complement in allergic asthma. Expert Rev. Clin. Immunol. 2010, 6, 269–277.
  236. Nimmerjahn, F.; Ravetch, J.V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 2008, 8, 34–47.
  237. Maceyka, M.; Payne, S.G.; Milstien, S.; Spiegel, S. Sphingosine kinase, sphingosine-1-phosphate, and apoptosis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2002, 1585, 193–201.
  238. Platt, F.M. Sphingolipid lysosomal storage disorders. Nature 2014, 510, 68–75.
  239. Messner, M.C.; Cabot, M.C. Glucosylceramide in Humans. Adv. Exp. Med. Biol. 2010, 688, 156–164.
  240. Melo, C.F.O.R.; de Oliveira, D.N.; Lima, E.D.O.; Guerreiro, T.M.; Esteves, C.Z.; Beck, R.M.; Padilla, M.A.; Milanez, G.P.; Arns, C.W.; Proenca-Modena, J.L.; et al. A Lipidomics Approach in the Characterization of Zika-Infected Mosquito Cells: Potential Targets for Breaking the Transmission Cycle. PLoS ONE 2016, 11, e0164377.
  241. Khan, I.; Katikaneni, D.S.; Han, Q.; Sanchez-Felipe, L.; Hanada, K.; Ambrose, R.L.; Mackenzie, J.M.; Konan, K.V. Modulation of Hepatitis C Virus Genome Replication by Glycosphingolipids and Four-Phosphate Adaptor Protein. J. Virol. 2014, 88, 12276–12295.
  242. Low, H.; Mukhamedova, N.; Cui, H.L.; McSharry, B.P.; Avdic, S.; Hoang, A.; Ditiatkovski, M.; Liu, Y.; Fu, Y.; Meikle, P.J.; et al. Cytomegalovirus Restructures Lipid Rafts via a US28/CDC42-Mediated Pathway, Enhancing Cholesterol Efflux from Host Cells. Cell Rep. 2016, 16, 186–200.
  243. Chotiwan, N.; Andre, B.G.; Sanchez-Vargas, I.; Islam, M.N.; Grabowski, J.M.; Hopf-Jannasch, A.; Gough, E.; Nakayasu, E.; Blair, C.D.; Belisle, J.T.; et al. Dynamic remodeling of lipids coincides with dengue virus replication in the midgut of Aedes aegypti mosquitoes. PLOS Pathog. 2018, 14, e1006853.
  244. Tanner, L.B.; Chng, C.; Guan, X.L.; Lei, Z.; Rozen, S.G.; Wenk, M.R. Lipidomics identifies a requirement for peroxisomal function during influenza virus replication. J. Lipid Res. 2014, 55, 1357–1365.
  245. Achdout, H.; Manaster, I.; Mandelboim, O. Influenza Virus Infection Augments NK Cell Inhibition through Reorganization of Major Histocompatibility Complex Class I Proteins. J. Virol. 2008, 82, 8030–8037.
  246. Hidari, K.I.P.J.; Suzuki, Y.; Suzuki, T. Suppression of the Biosynthesis of Cellular Sphingolipids Results in the Inhibition of the Maturation of Influenza Virus Particles in MDCK Cells. Biol. Pharm. Bull. 2006, 29, 1575–1579.
  247. Drews, K.; Calgi, M.P.; Harrison, W.C.; Drews, C.M.; Costa-Pinheiro, P.; Shaw, J.J.P.; Jobe, K.A.; Nelson, E.A.; Han, J.D.; Fox, T.; et al. Glucosylceramidase Maintains Influenza Virus Infection by Regulating Endocytosis. J. Virol. 2019, 93, 1–20.
  248. Carpinteiro, A.; Edwards, M.J.; Hoffmann, M.; Kochs, G.; Gripp, B.; Weigang, S.; Adams, C.; Carpinteiro, E.; Gulbins, A.; Keitsch, S.; et al. Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells. Cell Rep. Med. 2020, 1, 100142.
  249. Törnquist, K.; Asghar, M.Y.; Srinivasan, V.; Korhonen, L.; Lindholm, D. Sphingolipids as modulators of SARS-CoV-2 infection. Front. Cell Dev. Biol. 2021, 9, 1574.
  250. Vitner, E.B.; Achdout, H.; Avraham, R.; Politi, B.; Cherry, L.; Tamir, H.; Yahalom-Ronen, Y.; Paran, N.; Melamed, S.; Erez, N.; et al. Glucosylceramide synthase inhibitors prevent replication of SARS-CoV-2 and influenza virus. J. Biol. Chem. 2021, 296, 100470.
  251. Hong, B.Y.; Kim, E.Y.; Jung, S.-C. Upregulation of Proinflammatory Cytokines in the Fetal Brain of the Gaucher Mouse. J. Korean Med. Sci. 2006, 21, 733–738.
  252. Kim, E.Y.; Hong, B.Y.; Go, S.H.; Lee, B.; Jung, S.-C. Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease: Implications for neuronal loss in Gaucher disease. Exp. Mol. Med. 2006, 38, 348–356.
  253. Tybulewicz, V.L.J.; Tremblay, M.L.; Marca, L.; Willemsen, R.; Stubblefield, B.K.; Winfield, S.; Zablocka, B.; Sidransky, E.; Martin, B.M.; Huang, S.P.; et al. Animal model of Gaucher’s disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 1992, 357, 407–410.
  254. Vitner, E.B.; Salomon, R.; Farfel-Becker, T.; Meshcheriakova, A.; Ali, M.; Klein, A.D.; Platt, F.M.; Cox, T.M.; Futerman, A.H. RIPK3 as a potential therapeutic target for Gaucher’s disease. Nat. Med. 2014, 20, 204–208.
  255. Vardi, A.; Zigdon, H.; Meshcheriakova, A.; Klein, A.D.; Yaacobi, C.; Eilam, R.; Kenwood, B.M.; Rahim, A.A.; Massaro, G.; Merrill, A.H.; et al. Delineating pathological pathways in a chemically induced mouse model of Gaucher disease. J. Pathol. 2016, 239, 496–509.
  256. Kanfer, J.N.; Legler, G.; Sullivan, J.; Raghavan, S.S.; Mumford, R.A. The Gaucher mouse. Biochem. Biophys. Res. Commun. 1975, 67, 85–90.
  257. Enquist, I.B.; Bianco, C.L.; Ooka, A.; Nilsson, E.; Månsson, J.-E.; Ehinger, M.; Richter, J.; Brady, R.O.; Kirik, D.; Karlsson, S. Murine models of acute neuronopathic Gaucher disease. Proc. Natl. Acad. Sci. USA 2007, 104, 17483–17488.
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