Complex genetic signatures in immune cells underlie autoimmunity and inform therapy.Orrù V, Steri M, Sidore C, Marongiu M, Serra V, Olla S, Sole G, Lai S, Dei M, Mulas A, Virdis F, Piras MG, Lobina M, Marongiu M, Pitzalis M, Deidda F, Loizedda A, Onano S, Zoledziewska M, Sawcer S, Devoto M, Gorospe M, Abecasis GR, Floris M, Pala M, Schlessinger D, Fiorillo E, Cucca F.Nat Genet. 2020 Sep 14. doi: 10.1038/s41588-020-0684-4. Online ahead of print
We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10-11) independent association signals for 459 cell traits at 69 loci (52 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
We have been doing genetic studies for the past forty years, doing the same stuff, over and over again, but each time with new technologies. We now know up to 200 definitive genes and about another 200 likely candidates, but the number one was known before all this started. Yet 50 years on, this hasn’t led to any form of treatment related to that knowledge.
In this study they could see signatures of different genes that were associated with susceptibility to different autoimmune diseases. They suggested some targets for treatment for autoimmune disease. It is all so very complex.
For MS we have CD28 on T cells, but only a nutter would go anywhere near CD28 as a therapeutic target (Remember the elephant head problem trial). We have IL-2 receptor on T cells and we then a subset of memory B cells, memory B cells and CD40 on a B cell subset.
So look at the the different genes they pluck out of arthritis and MS
So you can say TNFSF13B on plasmablasts, CD19 on B cells, CD28 on T cells ITGAX is CD11c on macrophages, MS4A1 = CD20 so B cells, IL-2A=CD25 on T cells, CD27 on memory T cells and CD40 on macrophages. It is all very complex
There is so much data, it is so hard work out where to look. But if you are focused you could equally say CD28 =T cells but TNFSF13B= TACI = memory B cells, CD19= memory B cells signalling, ITGAX = memory B cells, MS4A1 = CD20 = memory B cells, IL-2RA = memory B cells, CD40 = memory B cells…..Maybe it is time to develop a therapy for memory B cells:-)
If this is wrong then move on.
But people say, “yeah right, it’s not the memory cells going up, it’s the regulatory B cells going down”. It’s how you view the world and it’s because MS B regs can’t control the T cells because they make less of an inhibitor cytokine. The reality will be somewhere in between….It’s all so complex:-)
Defective CD19+CD24hiCD38hi transitional B-cell function in patients with relapsing-remitting MS.Cencioni MT, Ali R, Nicholas R, Muraro PA.Mult Scler. 2020 Sep 14:1352458520951536
Background: Multiple sclerosis (MS) is characterized by central nervous system (CNS) infiltration of T and B cells, excess inflammatory cytokine and chemokine production and failure of immune regulation. CD19+CD24hiCD38hi transitional B cells producing interleukin (IL)-10 have been shown to suppress interferon-γ (IFNγ) and tumour necrosis factor-α (TNFα) production by CD4+ T cells and to be dysfunctional in autoimmune arthritis and systemic lupus erythematosus.
Objective: We hypothesized that transitional B-cell-dependent immune regulation could be defective in MS and examined their function in healthy subjects and patients with relapsing-remitting multiple sclerosis (RRMS).
Methods: A total of 62 healthy donors and 21 RRMS subjects donated peripheral blood for the study. IL-10-producing B cells, IFNγ and TNFα-producing T cells and proliferating T cells were quantified by flow cytometry.
Results: In healthy individuals, CD19+CD24hiCD38hi transitional B cells produce more IL-10 than CD19+CD24+CD38+ naive and CD19+CD24hiCD38- memory B cells and are able to suppress CD4+ T-cell proliferation and IFNγ and TNFα-production. In subjects with RRMS, CD19+CD24hiCD38hi transitional B cells produce significantly less IL-10 and to fail to suppress effector T-cell function.
Conclusion: CD19+CD24hiCD38hi transitional B cells physiologically represent the most potent regulatory B-cell subset and are functionally defective in patients with RRMS, an abnormality that may contribute to the immune pathological process.