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IKZF1 polymorphisms are associated with susceptibility, cytokine levels, and clinical features in systemic lupus erythematosus.
Chen, L, Niu, Q, Huang, Z, Yang, B, Wu, Y, Zhang, J
Medicine. 2020;(41):e22607
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Abstract
Ikaros family zinc finger 1(IKZF1) encodes a lymphoid-restricted zinc finger transcription factor named Ikaros that regulates lymphocyte differentiation and proliferation as well as self-tolerance. Increasing evidence indicates that IKZF1 could contribute to the pathogenesis of autoimmune diseases. Recent research has provided evidence that IKZF1 might correlate with Systemic lupus erythematosus (SLE), but no clear definition has been made yet. In this study, we focus on the relationship between IKZF1 polymorphisms and SLE susceptibility, cytokine levels, and clinical characteristics in the Chinese Han population.One thousand seventy-six subjects, including 400 SLE patients and 676 healthy controls, were included in this study. Three single nucleotide polymorphisms within IKZF1 containing rs4917014, rs11980379, and rs4132601 were genotyped in all subjects by an improved multiplex ligation detection reaction technique. 143 subjects from SLE patients were randomly selected for testing the levels of serum cytokines. The clinical characteristics of SLE patients were gathered and collated from medical records. The data were analyzed mainly using SPSS20.0 (SPSS lnc., Chicago, IL).Significant relationships were observed between rs4132601 and SLE susceptibility, CD40 ligand, and malar rash (P < .001, P = .04, and P = .01, respectively). In addition, significant relationships were observed between rs4917014 and susceptibility, granzyme B level, and hematological disorder in SLE (P = .005, P = .03 and P = .005, respectively).The results further support that IKZF1 may have an important role in the development and pathogenesis of SLE. Allele G of rs4132601 and rs4917014 is related to a decreased risk of SLE occurrence and associated with clinical features in SLE patients, including CD40 ligand level, granzyme B level, malar rash, and hematological disorder, which play important roles in disease progression.
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Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?
Bar-Or, A, Fawaz, L, Fan, B, Darlington, PJ, Rieger, A, Ghorayeb, C, Calabresi, PA, Waubant, E, Hauser, SL, Zhang, J, et al
Annals of neurology. 2010;(4):452-61
Abstract
OBJECTIVE To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS). METHODS B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS. RESULTS B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-alpha secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFalpha. INTERPRETATION We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.