ABSTRACT
Interleukin-21 (IL-21) upregulation was observed in Crohn's disease (CD) patients and was shown to contribute to ongoing mucosal inflammation in CD patients through stabilizing Th1 cell differentiation and IFN-γ production. Given the role of IL-21 in mediating adaptive B cell antibody responses in healthy individuals, we examined the effect of IL-21 upregulation in B cell responses in patients with active CD, including ileum, ileocolonic and colon subtypes, defined by the primary site of CD involvement. We first observed an upregulation of blood plasma IL-21 concentration and IL-21 production from CD4(+) T cells in CD patients compared to healthy individuals. The IL-21-expressing T cells were more concentrated in the CD4(+)CXCR5(+) compartment, both in unstimulated medium and after stimulation with SEB. ICOS and PD-1 expressions were also concentrated in the CD4(+)CXCR5(+) subset in CD patients. Since peripheral blood CD4(+)CXCR5(+) T cell-mediated antibody secretion is IL-21-dependent, we examined the plasma antibody concentration in CD patients and healthy controls. We found that CD patients had significantly higher plasma Ig level than healthy patients, with no significant differences between different CD subtypes. Higher plasma IL-21 concentration and increased IL-21 production from CD4(+) T cells were directly correlated with higher plasma antibody levels. Moreover, we found that IL-21 and CD4(+)CXCR5(+) T cells can directly enhance B cell antibody response in CD patients. Depletion of secreted IL-21 by sIL-21R addition compromised the CD4(+)CXCR5(+) T cell-mediated increase in antibody production. Together, our results demonstrated a novel role of IL-21 in mediating B cell inflammation in CD development.
Subject(s)
Antibody Formation/immunology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Crohn Disease/immunology , Crohn Disease/metabolism , Interleukins/metabolism , Adult , CD4 Lymphocyte Count , Case-Control Studies , Crohn Disease/blood , Crohn Disease/diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunophenotyping , Interleukins/blood , Male , Middle Aged , Receptors, CXCR5/metabolism , Severity of Illness Index , Young AdultABSTRACT
Type 2 diabetes (T2D) is a chronic metabolic disorder, which was also found to involve a series of inflammatory disorders, including accumulation of macrophages and T cells in the adipose tissue, increased proinflammatory cytokine production, shifting of macrophage composition toward M1-type, and skewing of peripheral blood T cells toward IL-17 productions. However, these studies were primarily conducted in obese mouse models and/or human subjects with higher BMI, and may not reflect the role of the immune system in non-obese T2D pathogenesis. Here, we examined T cell and monocyte cytokine expression and function in both non-obese and obese T2D patients. We found that IFN-g production by circulating T cells were increased in both non-obese and obese T2D subjects, while IL-17 is only upregulated in obese T2D subjects. Also, circulating monocytes from obese T2D subjects had significantly higher IL-6 production than their counterparts in non-obese T2D subjects. Moreover, monocytes from non-obese T2D subjects could support IFN-g but not IL-17 production in vitro, while that from obese T2D subjects supported both IFN-g and IL-17 production. Together, our results revealed that the role immune system plays in T2D pathogenesis is more complicated than previously thought, and is affected by the person's BMI.
