Ava Denton

 Background: Multiple sclerosis is a chronic immune-mediated demyelinating disease of the central nervous system affecting roughly 2.3 million people worldwide.² Myelin loss disrupts nerve conduction and contributes to progressive neurologic dysfunction.²  Although MS symptoms arise in the CNS, immune dysregulation outside the CNS may also influence disease activity, and MS is thought to develop through interactions among genetic and environmental factors.^2,3 Among the genetic contributors, HLA variation has been associated with MS susceptibility, suggesting that altered antigen presentation may influence downstream immune responses.¹ Because class II HLA molecules regulate antigen presentation to CD4-positive T cells, this provides a link to the autoreactive T-cell responses involved in MS pathogenesis and to B-cell activation.^1,6 More recent findings show that gut microbiota-specific IgA-positive B cells are enriched during active MS and may traffic from mucosal sites to the inflamed CNS, supporting a possible gut-brain immune axis, but the significance of gut IgA dysregulation and B-cell dysfunction in MS remains incompletely understood.⁷

Objective: This review aims to bring together current evidence on HLA‑linked antigen presentation, B-cell and IgA biology, and gut microbiome changes in multiple sclerosis, and to consider how these mechanisms may inform the use of anti‑CD20 therapies as a clinical target.^1-8

Search Methods: A literature search was conducted in PubMed using combinations of terms such as “multiple sclerosis,” “HLA,” “B cells,” “immunoglobulin A,” “gut microbiome,” and “anti‑CD20” to identify relevant articles published between 2017 and 2025.

Results: Studies show that HLA variation may contribute to MS susceptibility, with HLA-DPB1104:01 associated with increased risk and other alleles appearing protective, supporting a role for altered antigen presentation in disease development.¹ B cells were identified as professional antigen-presenting cells that express class II HLA molecules, process internalized antigens, and present peptide-HLA complexes to CD4-positive T cells, thereby supporting B-cell activation, class switching, and antibody production.⁶ In active MS, gut microbiota-specific IgA-positive B cells were increased and appeared to migrate from mucosal sites to the inflamed CNS.⁷ IgA produced by these CNS B cells bound MS-associated gut bacteria, including Akkermansia muciniphila, rather than brain tissue, supporting a gut-brain immune axis in which B cells originally activated by gut microbes may later participate in CNS immune dysregulation.⁷ In untreated, newly diagnosed MS, patients had a smaller proportion of IgA-coated gut bacteria despite similar total secreted fecal IgA compared with controls, with altered strain-specific IgA binding that included reduced binding to Faecalibacterium prausnitzii and increased binding to Monoglobus pectinilyticus.⁴ After 6 months of anti-CD20 therapy, several gut bacterial strains changed in abundance, and IgA coating of Akkermansia muciniphila shifted toward patterns seen in healthy controls.⁴ Anti-CD20 therapies, including ocrelizumab, deplete CD20-positive B cells, reduce inflammatory immune activity, and are associated with lower relapse rates and MRI lesion activity in relapsing MS; ocrelizumab is currently the only agent in this class approved for primary progressive MS.^5,8

Conclusions: HLA-associated risk supports altered antigen presentation as one contributor to MS susceptibility, while early disease shows abnormal IgA targeting of gut bacteria and partial normalization of some IgA-coating patterns after anti-CD20 therapy.^1,4 Together, these findings support the gut–immune axis as a clinically relevant pathway and potential therapeutic target in MS.^4,5,7

 Works Cited:

1.  Osoegawa K, Creary LE, Montero-Martín G, et al. High resolution haplotype analyses of classical HLA genes in families with multiple sclerosis highlights the role of HLA-DP alleles in disease susceptibility. Frontiers in Immunology. 2021;12:644838. doi:10.3389/fimmu.2021.644838.
2. Haki M, Al-Biati HA, Al-Tameemi ZS, Ali IS, Al-Hussaniy HA. Review of multiple sclerosis: Epidemiology, etiology, pathophysiology, and treatment. Medicine (Baltimore). 2024;103(8):e37297. doi:10.1097/MD.0000000000037297.
3. Esmaeil Amini M, Shomali N, Bakhshi A, et al. Gut microbiome and multiple sclerosis: New insights and perspective. International Immunopharmacology. 2020;88:107024. doi:10.1016/j.intimp.2020.107024.
4. Gupta VK, Janda GS, Pump HK, et al. Alterations in Gut Microbiome-Host Relationships After Immune Perturbation in Patients With Multiple Sclerosis. Neurol NeuroimmunolNeuroinflamm. 2025;12(2):e200355. doi:10.1212/NXI.0000000000200355
5. Carlson AK, Amin M, Cohen JA. Drugs Targeting CD20 in Multiple Sclerosis: Pharmacology, Efficacy, Safety, and Tolerability. Drugs. 2024;84(3):285-304. doi:10.1007/s40265-024-02011-w
6. Adler LN, Jiang W, Bhamidipati K, et al. The Other Function: Class II-Restricted Antigen Presentation by B Cells. Front Immunol. 2017;8:319. Published 2017 Mar 23. doi:10.3389/fimmu.2017.00319
7. Pröbstel AK, Zhou X, Baumann R, et al. Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis. Sci Immunol. 2020;5(53):eabc7191. doi:10.1126/sciimmunol.abc7191
8. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376(3):209-220. doi:10.1056/NEJMoa1606468