Letter: immune checkpoint inhibitor‐induced colitis—shouldn’t we be checking more often? Authors’ reply

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151368/1/apt15448_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151368/2/apt15448.pd

Autoimmune Enteropathy with a CD8\u3csup\u3e+\u3c/sup\u3e CD7\u3csup\u3e-\u3c/sup\u3e T-cell Small Bowel Intraepithelial Lymphocytosis: Case Report and Literature Review

Background Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE. Case Presentation We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement. Conclusions AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE

Peripheral nerve induces macrophage neurotrophic activities: regulation of neuronal process outgrowth, intracellular signaling and synaptic function.

Abstract Rat cortical neurons cultured in conditioned media from human monocyte-derived macrophages (MDM) show increased neuronal protein synthesis, neurite outgrowth, mitogen-activating protein kinase activity, and synaptic function. Neurotrophic properties of human MDMconditioned media are significantly enhanced by human peripheral nerve and to a more limited extent by CD40 ligand pre-stimulation. Such positive effects of MDM secretions on neuronal function parallel the secretion of brain-derived neurotrophic factor (BDNF). MDM activation cues may serve to balance toxic activities produced during neurodegenerative diseases and thus, under certain circumstances, mitigate neuronal degeneration.

Autoimmune enteropathy with a CD8+ CD7- T-cell small bowel intraepithelial lymphocytosis: case report and literature review

<p>Abstract</p> <p>Background</p> <p>Adult onset autoimmune enteropathy (AIE) is a rare condition characterized by diarrhea refractory to dietary therapy diagnosed in patients with evidence of autoimmune conditions. Auto-antibodies to gut epithelial cells and other tissues are commonly demonstrated. Despite increasing awareness, the pathogenesis, histologic, immunologic and clinical features of AIE remain uncertain. There remains controversy regarding the diagnostic criteria, the frequency and types of auto-antibodies and associated autoimmune conditions, and the extent and types of histologic and immunologic abnormalities. CD4+ T-cells are thought to at least responsible for this condition; whether other cell types, including B- and other T-cell subsets are involved, are uncertain. We present a unique case of AIE associated with a CD8+CD7- lymphocytosis and review the literature to characterize the histologic and immunologic abnormalities, and the autoantibodies and autoimmune conditions associated with AIE.</p> <p>Case Presentation</p> <p>We present a case of immune mediated enteropathy distinguished by the CD8+CD7- intra-epithelial and lamina propria lymphocytosis. Twenty-nine cases of AIE have been reported. The majority of patients had auto-antibodies (typically anti-enterocyte), preferential small bowel involvement, and predominately CD3+ CD4+ infiltrates. Common therapies included steroids or immuno-suppressive agents and clinical response with associated with histologic improvement.</p> <p>Conclusions</p> <p>AIE is most often characterized (1) IgG subclass anti-epithelial cell antibodies, (2) preferential small bowel involvement, and (3) CD3+ alphabeta TCR+ infiltrates; there is insufficient evidence to conclude CD4+ T-cells are solely responsible in all cases of AIE.</p

Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy

IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade

Dendritic cell- derived TGF- β mediates the induction of mucosal regulatory T- cell response to Helicobacter infection essential for maintenance of immune tolerance in mice

BackgroundHelicobacter pylori infection leads to regulatory T- cell (Treg) induction in infected mice, which contributes to H. pylori immune escape. However, the mechanisms responsible for H. pylori induction of Treg and immune tolerance remain unclear. We hypothesized DC- produced TGF- β may be responsible for Treg induction and immune tolerance.Materials and MethodsTo test this hypothesis, we generated TGF- β- DC mice (CD11c+ DC- specific TGF- β deletion) and assessed the impact of DC- specific TGF- β deletion on DC function during Helicobacter infection in vitro and in vivo. To examine the T cell- independent DC function, we crossed TGF- β- DC mice onto Rag1KO background to generate TGF- β- DCxRag1KO mice.ResultsWhen stimulated with H. pylori, TGF- β- DC BMDC/splenocyte cocultures showed increased levels of proinflammatory cytokines and decreased levels of anti- inflammatory cytokines compared to control, indicating a proinflammatory DC phenotype. Following 6 months of H. felis infection, TGF- β- DC mice developed more severe gastritis and a trend toward more metaplasia compared to TGF- βfl/fl with increased levels of inflammatory Th1 cytokine mRNA and lower gastric H. felis colonization compared to infected TGF- βfl/fl mice. In a T cell- deficient background using TGF- β- DCxRag1KO mice, H. felis colonization was significantly lower when DC- derived TGF- β was absent, revealing a direct, innate function of DC in controlling H. felis infection independent of Treg induction.ConclusionsOur findings indicate that DC- derived TGF- β mediates Helicobacter- induced Treg response and attenuates the inflammatory Th1 response. We also demonstrated a previously unrecognized innate role of DC controlling Helicobacter colonization via a Treg- independent mechanism. DC TGF- β signaling may represent an important target in the management of H. pylori.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163641/2/hel12763.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163641/1/hel12763_am.pd