Marginal Zone Precursor-Like in Diseases: History
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Johanne Poudrier

Marginal zone (MZ) B-cells are innate-like, and possess a polyreactive B-cell receptor (BCR) and several pattern recognition receptors (PRR). They are known to generate low-affinity first-line antibody responses against invading pathogens such as encapsulated bacteria.

  • MZp

1. Introduction

Marginal zone (MZ) B-cells are innate-like, and possess a polyreactive B-cell receptor (BCR) and several pattern recognition receptors (PRR) [1][2]. They are known to generate low-affinity first-line antibody responses against invading pathogens such as encapsulated bacteria [3].

2. MZps and Similar Populations in Other Diseases

2.1. Autoimmune Diseases

As mentioned above, in the HIV context, MZps share some similarities with a heterogeneous T-bet+CD11c+ population reported to be increased in the context of chronic infections and inflammatory conditions; which profile is reminiscent of “age-associated B-cells”, a cell population first described in mice [4][5]. These T-bet+CD11c+ cells have been associated with disease progression and clinical manifestations in SLE patients [6][7]. Interestingly, women are more affected than men by autoimmune diseases [8]. It is known that estrogen promotes the activation and expansion of autoreactive MZ B-cells in both mice and humans [2].
As observed for the Breg profile of blood MZp from HIV-infected individuals, deregulations of different Breg populations are also associated with autoimmunity, such as those observed in SLE, multiple sclerosis (MS) and RA [9]. For example, CD19+CD24highCD38high B-cells from the blood of SLE-afflicted individuals lose the capacity to control TNF-α and IFN-γ production by CD4+ T cells [10]. Similarly to the HIV context, in all these cases, BAFF was found in excess, and played a role in the development of autoimmunity [9][10][11][12]. In fact, in SLE and SS, excess BAFF positively correlates with the level of circulating auto-antibodies [11].

2.2. Atherosclerosis

Chronic inflammation in PLHIV has been associated with the premature development of age-associated comorbidities such as atherosclerosis, the main risk factor for cardio-vascular disease (CVD) [13][14][15]
Atherosclerosis is, by its nature, an inflammatory disease; and the persistent chronic inflammation that prevails in PLHIV may fuel its early development. As such, when matched for traditional risk factors, HIV-infected individuals had a higher chance of developing CVD when compared to HIV-uninfected individuals [13][14][16].
The role of BAFF in atherosclerosis development is complicated and poorly explored in humans (most of the research was traditionally conducted in mice). For instance, in the aforementioned research, BAFF neutralization aggravates atherosclerosis, while BAFF overexpression attenuates this disease [17][18]. This has been attributed to TACI-expressing cells, such as MZ B-cells, which express high levels of this receptor. Indeed, MZ B-cells were shown to possess an atheroprotective role due to PD1-PD-L1 interactions with Tfh cells, allowing for a better control of GC reactions, a role that was attributed to MZ B-cell NR4A1 expression [19][20]. Moreover, FO B-cells are considered to be atherogenic, as they generate GC responses and, subsequently, IgG directed against oxidized LDL (oxLDL) [21]. Thus, in the context of MZ and MZp deregulation, such as the one found in HIV infection, it is possible to assume that these cells lose their capacity to maintain their immune surveillance capacities, contributing to the early onset of atherosclerosis in HIV-infected individuals.
In humans, excess BAFF was also found to correlate with CVD development in autoimmune diseases such as SS and SLE. As a matter of fact, CVD was found to be the major cause of death in individuals afflicted by SLE [22][23]. As such, BAFF, when in excess, could be related to the premature development of CVD; this can either be directly—through it being overtly produced by adipocytes and acting as an adipokine linking obesity and inflammation, and by contributing to the apoptosis of endothelial cell progenitors (a process known as endothelial dysfunction, a triggering factor for atherosclerosis development)—or indirectly, by altering the atherosclerosis immune surveillance processes, which are usually warranted by Breg populations such as MZ B-cell populations [24][25].

2.3. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and Other Viral Infections

It was found that individuals who had died of the SARS-CoV-2 infection had a lack of GC in their lymphoid organs, which was partly explained by the downregulation of the transcription factor B-cell lymphoma 6 (Bcl-6) by B-cells and T-cells [26]. This loss of GC was associated with increased frequencies of T-bet+CD11c+ extra-follicular B-cells, which have been associated with a strong production of auto-antibodies and poor disease outcome in individuals infected with SARS-CoV-2 [27]. Indeed, auto-antibodies directed against interferons are one of the key triggering events to critical COVID-19 pneumonia and death in patients who develop this disease [28]. Unsurprisingly, BAFF was found to be elevated and to persist in individuals with severe disease [29]. Of interest is the fact that levels of APRIL were found to be elevated in individuals who had recovered from the infection [29][30].
Reports of an extra-follicular population sharing similar features with MZp, known as CD21low MZ-like B-cells, was found to be increased in individuals infected with hepatitis C virus (HCV) [31]. This population expressed an autoreactive BCR and was correlated with increased autoimmunity in the HCV context [31].
Overall, most chronic inflammatory conditions are associated with excessive BAFF levels and polyclonal B-cell activation, at the expense of functional immune surveillance. If not addressed therapeutically, these could lead to long term and/or persistent autoimmune manifestations and life-threatening co-morbidities.

2.4. Malignancies Associated with MZ Deregulations

One complication often associated with deregulations of MZ B-cell populations is Marginal Zone Lymphoma (MZL), which is the second most common non-Hodgkin’s lymphoma and which possess varying manifestations (according to the WHO classification), such as splenic MZL, nodal MZL and extra-nodal MZL of the MALT, depending on the initiating site [32][33]. Many of these lymphomas appear due to mutations on genes associated with MZ differentiation, such as NOTCH2, as well as mutations on genes involved in the BCR signaling and NF-kB pathways [34][35]. The differential diagnosis between the myriad of different MZL manifestations is complex and requires several investigations, notably immune profiling and genetic tests [36].
Non-Hodgkin’s lymphomas are highly represented in PLHIV. Even though MZL is not an AIDS-defining lymphoma, its incidence is indeed higher when compared to healthier populations [37][38]. In PLHIV, the immune-incompetence caused by the HIV-infection and chronic inflammatory condition, despite HAART, may be involved in the development of these types of lymphomas. As such, chronic inflammation and autoimmune manifestations were found to be related to the development of MZL malignancy in PLHIV as well as in individuals diagnosed with SLE, SS and RA [39][40]. Additionally, MZL development has been associated with chronic infection by Helicobacter pylori and Borrelia burgdoferi in the case of gastric MZL and subcutaneous MZL, for instance [37][41]. Interestingly, certain types of MZL are also associated with a “biased” usage of Ig heavy chains, implying that the capacity to respond to certain types of antigens is a predicting risk for the development of these diseases [42][43]. Moreover, it has been shown that CSR and SHM, mediated by the upregulation of Activation-induced cytidine deaminase (AID) due to inflammation and increased NF-κB expression, induce genomic instability, driving carcinogenesis [44]. Thus, chronic activation of MZ B-cells in the context of autoimmunity or in the HIV context, for instance, could be a triggering factor for the development of this type of malignancy. As such, the recent report that NR4As are severely and significantly downregulated in blood MZp from HIV-infected progressors may constitute prognostic markers for MZL development in these individuals, as NR4A1 has been reported to be severely downregulated in aggressive and indolent human B-cell lymphomas [45].
One of the key phenotypical differences between FO and MZ B-cells is the expression of IgD, the latter expressing lower levels of this molecule than the former [1]. However, in certain types of MZL, such as splenic MZL, tumor cells heavily express IgD, which could be used as a marker to distinguish splenic MZL cells from other types of MZL that happened to invade the spleen [46]. Notably, it has been shown that in a model of constitutive induction of NOTCH2, FO B-cells could differentiate into MZ B-cells [47]. As such, mutations triggering the expression of this molecule or mutations in its master regulator, Kruppel-like factor 2 (KLF2)—both of which were found in MZL—could be related to the generation of atypical MZ, leading to the development of this type of cancer [37][48]. Interestingly, the constitutive induction model of NOTCH2 induced a strong downregulation of KLF2 [47]. Thus, more studies need to be conducted in this field.

3. Possible Therapeutic Avenues

Since HAART is not sufficient to cease chronic inflammation and the associated development of co-morbidities and autoimmune manifestations in HIV-infected individuals, the addition of other drugs could be contemplated as an adjunct to HAART; this might help to lower the inflammatory burden and restore immune competence, especially given the fact that, nowadays, those individuals live longer. In this view, lowering BAFF levels with reagents such as the FDA-approved Belimumab (Benlysta) could be contemplated, as this antibody is currently used in the treatment of SLE and shows satisfactory results in the improvement of disease progression [49]. Other drugs, such as dihydroergotamine (DHE), that upregulate NR4A expression levels, have potential in treating acute myeloid lymphoma (AML) through induction of apoptosis of cancerous cells; they could be tested to try to either restore the Breg function of MZps or to induce their apoptosis [50].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23063372

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