Immune Response and Therapeutic Vaccination against Helicobacter pylori

Abstract Helicobacter pylori (H. pylori) is a gram-negative bacterium, considered one of the significant discoveries about 40 years ago, and was isolated and cultured from the human stomach. H. pylori has infected more than half of the human population, making it one of the most well-known human pathogens. The front line of immune response starts with innate recognition of H. pylori and its mediators and intracellular signaling by gastric epithelial cells in which they recognize and respond to bacterial products such as flagella, lipopolysaccharides, and peptidoglycan. The inflammatory response is followed by the recruitment of various cells of the innate and adaptive immune system. Cytokines including IL-12, IL-23, and TGF-β direct the polarization of CD4+ T helper cells to Th1, Th17, and Treg, respectively. The clinical symptoms that may occur as a result of H. pylori infection linked to the virulence factors of the bacteria, the genetic factors of the host, and the immune responses. Specific antigens have been found as part of these crucial virulence factors. The specific antigens may play a role in the development of an effective vaccine to eradicate H. pylori infection. Innate and adaptive immunity and genetic factors have an important place in understanding the host response mechanisms, elucidating the pathogenesis of the disease, and developing new targeted therapy approaches. Thus, the aim of this study is to understand immune responses and investigate the potential therapeutic vaccination against H. pylori

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency

Background Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. Methods The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT(FH)) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. Results Mean age at disease onset was 38 +/- 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4(+) T cells, Treg, and cT(FH) cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years). Conclusion This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency

Evolution and long-term outcomes of combined immunodeficiency due to CARMIL2 deficiency

Background Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. Methods The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cT(FH)) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. Results Mean age at disease onset was 38 +/- 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4(+) T cells, Treg, and cT(FH) cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years). Conclusion This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency

Comparing the levels of CTLA-4-dependent biological defects in patients with LRBA deficiency and CTLA-4 insufficiency

Background Lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency and cytotoxic T-lymphocyte protein-4 (CTLA-4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long-term follow-up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA-4 insufficiency. Methods Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (T-FH), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post-stimulation. Results LRBA-deficient patients (n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA-4 insufficiency (n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non-transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA-4-insufficient patients (p = 0.04). The T-cell subsets showed more deviation to memory cells in CTLA-4-insufficiency, accompanied by low percentages of Treg and dysregulated cT(FH) cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cT(FH) frequencies. Baseline CTLA-4 expression was significantly diminished in LRBA deficiency and CTLA-4 insufficiency, but significant induction in CTLA-4 was observed after short-term T-cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA-4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). Conclusion This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA-4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA-4 pathway