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IgG N-glycan Signatures as Diagnostic and Prognostic Biomarkers: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Mary Comunale.

IgG N-glycans are an emerging source of disease-specific biomarkers. The continued development of glycomic databases and the evolution of glyco-analytic methods have resulted in increased throughput, resolution, and sensitivity. IgG N-glycans promote adaptive immune responses through antibody-dependent cellular cytotoxicity (ADCC) and complement activation to combat infection or cancer and promote autoimmunity. In addition to the functional assays, researchers are examining the ability of protein-specific glycosylation to serve as biomarkers of disease. 

  • immunoglobulin G
  • IgG
  • N-glycan
  • diagnostic
  • prognostic

1. IgG N-Glycans in Healthy Humans

Serum glycoproteins contain many different glycan moieties, but the overall protein glycosylation pattern for each protein remains constant in the healthy state. Total serum IgG N-glycosylation profiles from healthy humans fall within a specific range for each of the major N-glycan classes: 35% agalactosylated, 35% mono-galactosylated, 15% di-galactosylated, 10% mono- and di-sialylated, 10% bisecting, and 90% core-fucosylated [23,48][1][2]. Conversely, in disease glycosylation can be dynamic and reflect specific disease states.
The healthy IgG N-glycan profile often reflects an immune system without infection, cancer, or an autoimmune condition. Age impacts the IgG N-glycan profile; pediatric age ranges gain galactose into young adulthood [49][3] while older adults decrease galactose content [50,51,52][4][5][6]. Differences in IgG N-glycosylation also arise when comparing cohorts stratified by: males vs. females [53[7][8],54], diet [55][9], menopause [56[10][11],57], pregnancy [17][12], physical exercise [58][13], country of residence [59][14], and body mass index [60,61,62,63,64][15][16][17][18][19]. As the following sections will describe, the IgG N-glycan profile can shift dramatically beyond the confounding effects listed above when responding to infection, autoimmunity, or cancer. However, it is important to account for the innate differences in IgG N-glycan profiles when developing diagnostic algorithms.

2. IgG N-Glycans Altered during Infectious Disease

Infectious and inflammatory diseases are associated with antigen-specific IgG, IgG subclasses (IgG1-4), and total IgG N-glycosylation profile alterations. Characterizing IgG N-glycans during disease states compared to healthy control cohorts can accurately reflect the host’s immune status [65][20]. Moreover, longitudinally profiling a patient’s IgG N-glycosylation following diagnosis and during treatment can track patient immune responses [66][21].

2.1. IgG N-Glycans Altered during Viral Infections

Viruses require host machinery to replicate and can be classified depending on their replication strategy, tissue tropism, envelope, chronicity, and carcinogenic potential [106][22]. Viruses are incapable of glycosylation; however, many viral proteins contain N-linked glycans that are added by hijacking the host cell machinery. While the diagnosis of viral infections is mainly accomplished through the detection of viral loads [107][23], the prognosis of a patient and potential mechanisms promoting disease responses via IgG N-glycosylation has received attention in the literature in recent years.

2.2. Dengue Fever

Acute viral infections are known to alter IgG N-glycan profile in infected humans. Dengue (DENV) is a flavivirus that induces the host to produce antibodies that can drive pathology through antibody-dependent enhancement upon reinfection [75,108][24][25]. The glycosylation of IgG antibodies during a severe DENV re-infection offers a clear example of Fc N-glycans driving a disease phenotype. During severe DENV infections, IgG N-glycans profiles become proinflammatory—associated with lower fucosylation, more agalactose exposure, and lower sialylation [75][24]. As a result of the glycosylation, DENV antibodies produced during severe disease promote increased complement deposition and ADCC in humans. Severe DENV survival is strongly associated with a higher proportion of core-fucose on IgG1 in humans. In vivo functional experiments demonstrate that afucosylated IgG1 produced in response to DENV infection activates platelets and leads to significant thrombocytopenia due to FcγR IIIA pathway activation. In addition, maternal Dengue antigen-specific IgG fucosylation levels predict an infant’s susceptibility to a severe Dengue infection [76,77][26][27]. Thus, IgG N-glycan profiles can predict susceptibility to severe DENV infection and play a role in disease pathogenesis.

2.3. Influenza and RSV

Influenza viruses are associated with seasonal epidemics in humans, leading to more than 100,000 deaths annually [109][28]. Annual influenza vaccinations are deployed to protect older and immunocompromised individuals within the population. While a plethora of research focuses on the effect of influenza vaccination on serum IgG glycosylation and therapeutic IgG antibody glycosylation, there are few studies that examine the host IgG glycan response to a natural infection. One study looked at patients hospitalized for influenza infection and determined that the patient serum IgG N-glycosylation exhibited increased sialic acid while also decreasing core-fucose content [68][29]. The decreased fucosylation was associated with heightened ADCC while the increase in sialic acid was associated with antigen affinity maturation.
Respiratory Syncytial Virus (RSV) is a source of severe lower respiratory tract infections in young children, leading to over 100,000 estimated worldwide deaths annually [110][30]. Antigen-specific IgG from infants was examined for Fc glycosylation, revealing that the degree of fucosylation correlates with the natural killer (NK) cell activation [69][31]. Furthermore, RSV-specific IgG isolated from severe RSV infants induces lower levels of IFN-γ compared to healthy age-matched controls.

2.4. SARS-CoV-2

SARS-CoV-2 (COVID-19) has impacted the world significantly since its outbreak in late 2019, killing more than 14 million between 2020 and 2021 [111][32]. RT-PCR and rapid antigen tests have helped to accurately diagnose patients early in the disease progression [112][33], yet predicting a patient’s outcome and hospitalization requirements remain challenging. A case–control study determined that during severe disease, IgG N-glycans lost significant levels of fucose and had lower levels of sialic acid content compared to patients with a mild case of COVID [28][34]. Because IgG N-glycans can promote complement deposition and ADCC, the N-glycan profile could identify patients in a highly proinflammatory state and associated with a heightened risk for a cytokine storm. Other studies have confirmed a lower level of sialylation and galactosylation with a concomitant increase in agalactose content associated with hospitalized COVID-19 patients who did not survive [68,70][29][35].
In addition to total IgG N-glycan profiles, antigen-specific IgG N-glycan profiles has been isolated and analyzed, affording a more detailed perspective of the B-cell response to COVID. When anti-spike protein IgG1 was analyzed, there was a significant loss of galactose and sialyation with concurrent increased bisecting GlcNAc glycans in patients [71][36]. The spike-specific IgG1 N-glycosylation patterns could predict, at the time of hospital admission, which patients would require ICU admission in the following days. COVID-19 severity has been linked to an overactivation of the ADCC pathway by afucosylated anti-spike IgG N-glycans [72][37]. Moreover, a longitudinal study of severe- vs. mild-COVID, that included four European cohorts, identified a loss of sialic acid and bisecting N-glycans, and a rise in agalactose content in the total IgG profile of severe COVID patients [73][38]. These results were affirmed by another study that also found lowered sialylation and more agalactose content on IgG was associated with a poor prognosis leading to an AUC of 0.72 [74][39]. Taken together, these results support the notion that IgG N-glycans play a role in the pathogenesis of serve COVID and are a valuable tool to triage patients who will require more intense medical support during this viral respiratory illness.

2.5. HIV

Chronic viral diseases such as HIV can impact the health of the patient over time and are monitored for disease progression. Understanding human immunodeficiency virus (HIV) progression and viral rebound is important in developing treatment and vaccination strategies [113][40]. HIV rebound during antiretroviral therapy (ART) is strongly associated with patients’ levels of di-galactosylated and agalactosylated IgG in two geographically distinct cohorts [97,98][41][42]. IgG N-glycan profiles also differed between adolescents with HIV that progressed to more severe immunocompromised states compared to HIV non-progressors [99][43]. Pediatric HIV non-progressors exhibited IgG Fc N-glycosylation associated with a more potent effector function. Both progressor and non-progressor HIV pediatric cohorts exhibited more sialyation on gp120-specific IgG Fc regions. This sialyation was associated with increased broad neutralizing antibody (bnAb) breadth and suggests that increased sialyation on IgG may promote affinity maturation in children as compared to the lower bnAb production in adults. The authors go on to postulate IL-21 stimulation of B cells by T follicular helper cells could promote increased sialyation and galactosylation of IgG [44]. Thus, IgG N-glycans can add clinical value when predicting viral rebound and driving antigen-specific responses to HIV infection.

2.6. HBV

Hepatitis caused by the hepatitis B virus (HBV) is highly prevalent and leads to an estimated 820,000 deaths from liver fibrosis and progression to liver cancer [114,115][45][46]. Patients require monitoring over their lifetime for disease progression. However, effective monitoring requires costly ultrasounds along with bloodwork every six months. Diagnostics such as the GlycoTest have identified increased fucosylation on other serum glycoproteins leading to liver cancer and are currently in clinical trials [116][47]. Previous studies of IgG N-glycosylation during Chronic hepatitis B are associated with increased agalactose content on the Fc region of IgG [100][48]. Moreover, the aberrant glycosylation of IgG was reversed in noncirrhotic chronic hepatitis B patients following antiviral therapy. Recent studies of IgG N-glycans have identified specific changes in IgG subclasses 1–4 that discriminate cohorts of healthy controls, early fibrosis, and significant fibrosis with sensitivities of 92%, 84%, and 94%, respectively [104][49]. Taken together, IgG N-glycans are a valuable resource to determine the patient’s prognosis, stage of disease, and treatment response while avoiding the need for invasive liver biopsies.

3. IgG N-Glycans Altered during Bacterial and Parasitic Infections

Few bacterial or parasitic infections have been analyzed for their host response of IgG N-glycosylation. This may be due to many bacterial infections being acute inflammatory conditions that are often identified and treated with the appropriate antibiotic rather than chronic infections [117][50]. Although bacterial latency and chronicity in humans is less common in bacterial infections than with viruses, they still represent an enormous global disease burden and adversely impact patient quality of life.

3.1. Tuberculosis

Tuberculosis (TB) is first bacterial infection to have a comprehensive serum IgG N-glycosylation analysis completed. TB is a bacterial infection that can lead to chronic, life-long infection with one out of three people currently infected with TB globally [118][51]. Biomarkers of active versus latent TB have been elusive, resulting in patients with active, contagious disease not being effectively triaged for treatment. IgG N-glycans were used to discriminate between a latent TB infection and an active TB infection by tracking the loss of galactose and sialic acid content on the IgG Fc region of patients with active TB in two separate cohorts [94][52]. IgG N-glycans reverted to the less inflammatory, more galactosylated profile in patients who had received treatment for TB [95][53], indicating usefulness in determining disease resolution. Lastly, measuring the ratio of agalactose to galactosylated IgG N-glycans detected TB patients compared to healthy controls with a sensitivity of 76% and a specificity of 71% [96][54].

3.2. Lyme Disease

Patients with acute Lyme disease (LD) are often seronegative early during the disease and risk disease progression if not treated with antibiotics promptly. Total IgG N-glycosylation was significantly altered in a cohort of acute Lyme disease patients [67][55]. Surprisingly, the N-glycans displayed reduced agalactose and increased di-galactose content during the acute stage which led to a sensitivity of 75%, and specificity of 100% for acute LD discrimination from healthy controls. Moreover, in patients who received treatment and returned to donate serum after 70–90 days of convalescence, the N-glycans on IgG could be used to discriminate between treated and acute Lyme disease with a sensitivity and specificity of 100%. This suggests that IgG N-glycans can differentiate disease states during Lyme disease and may identify patients successfully responding to antibiotic treatment.

3.3. Meningococcus

Pediatric patients with meningococcal sepsis are at a heightened risk of morbidity and mortality. Prognostic indicators of disease outcomes are of great interest and could aid to initiate appropriate treatments [119][56]. Recent work identified that IgG1 fucosylation was reduced and bisection was increased in patients aged 0 to 3.9 years of age compared to healthy age-matched controls [52][6]. Moreover, when meningococcal septic patients aged 0–3.9 years of age were stratified into severe and non-severe cohorts, hybrid type N-glycans on IgG1 and IgG2/3 were significantly reduced while all IgG isotypes also contained significantly lower sialyation. The IgG Fc glycosylation is also associated with other inflammatory markers including thrombocyte levels, fibrinogen, and the cytokine IL-6. Hybrid structures on IgG2/3 had significantly positively correlated relationships between CRP and leukocyte levels.

3.4. Malaria

Malaria is a protozoan parasitic infection spread to humans from the bite of an infected mosquito, costing hundreds of thousands of mostly young children’s lives annually in endemic areas [120][57]. When Larsen et al. characterized the glycosylation of total IgG from people in malaria-endemic regions, they detected high levels of core-fucose, similar to non-malaria endemic region total IgG fucosylation. When they isolated malaria antigen-specific IgG1 developed from natural infection, they detected significantly lower levels of core-fucose [105][58]. In contrast, antigen-specific IgG1 produced in response to a malarial subunit vaccination did not induce lower core-fucose content on antigen-specific IgG1. The group demonstrated that only afucosylated IgG1 could induce ADCC against the malarial antigen, indicating the need to design malarial vaccines that better mimic natural infection to produce effective IgG with lower core-fucose content.

4. IgG N-Glycans Altered in Cancer

Early diagnosis of cancer is crucial for positive clinical outcomes, particularly in cancers not easily identified through annual screenings or those located in soft tissues that lack a clear diagnostic presentation [134][59]. IgG N-glycan profile analysis has been demonstrated as a noninvasive method to identify various malignancies in humans. Below are recent reports applying IgG N-glycans to discriminate between cancer stages and healthy controls.

4.1. Breast and Cervical Cancer

Many cancers in females are challenging to diagnose early in disease progression, and novel biomarkers could increase survival rates by initiating treatment earlier [135][60]. Stage II breast cancer patients were differentiated from healthy controls using the increased content of IgG N-glycans FA2G0 (AUC of 0.96) and FA2BG0 (AUC of 0.92) [87][61]. In addition, endometrial cancer (EC) patient IgG N-glycans in combination with BMI and age differentiated EC patients from healthy controls with an AUC of 0.87. This discrimination between healthy control and EC patients was driven by lower galactose and sialic acid content [88][62]. Serum IgG fucosylation decreased in women with cervical intraepithelial neoplasia I (CIN I). Females with cervical cancer were detected using a high-throughput enzyme-linked lectin assay (ELLA) [89][63]. Healthy controls were discriminated from CIN I patients using a fucose-quantitating ELLA with a sensitivity of 73% and a specificity of 62%. Meanwhile, the IgG fucose content discriminated healthy controls from cervical cancer patients with a sensitivity of 87% and a specificity of 72%.

4.2. Thyroid Cancer

Many cancers present in both males and females also lack sensitive early biomarkers and would benefit from better screening tests. Thyroid cancer (TC) is the most common cancer of the endocrine system and currently lacks biomarkers to detect the early stages of TC, instead, diagnosis is achieved using invasive procedures [136][64]. IgG N-glycan profiles from TC patients have been assayed to provide a differential diagnosis of early thyroid cancer. A comparison of IgG N-glycans from early thyroid cancer patients, healthy controls, and patients with benign thyroid nodules led to an AUC of 0.809 driven by an increase in bisecting, non-sialylated N-glycans [90][65].

4.3. Colorectal Cancer

Early colorectal cancer (CRC) arises from precancerous advanced colonic adenomas (PACA) [137][66]. Noninvasive, early biomarkers of colorectal cancer are urgently needed to initiate treatment for CRC patients and prevent metastasis. IgG N-glycan profiles could discriminate healthy controls from PACA (AUC = 0.84, sensitivity 61%, specificity 85%) and healthy controls from CRC (AUC = 0.84, sensitivity 72%, specificity 87%) [91][67]. IgG N-glycans discrimination of healthy controls compared to CRC patients was improved when combined with the traditional carcinoembryonic antigen (CEA) CRC marker. The IgG N-glycan profiling method outperformed two other noninvasive CRC screening methods, septin9 [138][68] and FIT [139][69]. Moreover, CRC patients who would experience a postoperative CRC relapse were discriminated from postoperative non-relapsing CRC patients with an AUC of 0.87 using the IgG N-glycan profiling method.

4.4. Pancreatic Cancer

Differentiation between pancreatic ductal adenocarcinoma (PDAC) and autoimmune pancreatitis (AIP) can be very difficult because both diseases share clinical, biochemical, and imaging characteristics [140][70]. Yet, IgG N-glycans discriminated PDAC from AIP with a diagnostic accuracy of 93% using a classification and regression tree (CART) validated with a second blinded cohort [85][71]. The group reported increased agalactosylation of IgG1 in the PDAC cohort which contrasted with increased sialylation and fucosylation ratios detected in the AIP cohort. Another study of pancreatic cancer IgG N-glycans detected early stages of the disease with an AUC of 0.91 while the traditional cancer antigen 19-9 (CA19-9) biomarker of PDAC obtained an AUC of 0.81 [93][72].

4.5. B-Cell Cancer

Lastly, IgG N-glycan profiles also change during B-cell cancers. Stages of plasma cell disorders leading to multiple myeloma begin with monoclonal gammopathy of undetermined significance (MUGS), progressing to smoldering myeloma (SMM), and lastly to multiple myeloma (MM). The IgG N-glycans present at each of these stages was found to correlate disease severity with increased agalactosylated and afucosylated N-glycan content [92][73]. MM in remission appeared to have recovered more of the normal galactose and fucose content, closely correlating with the traditional M-protein biomarker of MM. The agalactose content subsequently increased during MM relapse. In the SMM stage, more galactose and sialic acid was observed on IgG Fc regions compared to either MUGS or MM. Taken together, IgG N-glycan profiles can stage plasma cell disorder disease and identify patients who relapse following treatment.

 

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