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Immune control of Mycobacterium tuberculosis depends on interferon γ (IFN-γ)-producing CD4⁺ lymphocytes. Previous studies have shown that T cells from patients with tuberculosis produce less IFN-γ, compared with healthy donors, in response to mycobacterial antigens, although IFN-γ responses to mitogens are preserved. In this work, we found that M. tuberculosis-induced IFN-γ production by human T cells correlated with phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38. Moreover, the majority of IFN-γ-producing T cells expressed signaling lymphocyte activation molecule (SLAM), and SLAM activation further increased ERK phosphorylation. Interestingly, patients with tuberculosis had delayed activation of ERK and p38, and this was most marked in patients with the poorest IFN-γ responses (ie, low responders). Besides, SLAM signaling failed to phosphorylate ERK in low responders. Our findings suggest that activation of p38 and ERK, in part through SLAM, mediates T-cell IFN-γ production in response to M. tuberculosis, a pathway that is defective in patients with tuberculosis.

CD4+ T follicular helper cells ( T F H ) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). T F H lymphocytes were characterized by expression of CXCR5 and PD-1. T F H were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and T F H reg were similar in both CVID groups and in N. T F H responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of T F H cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that T F H are functional in CVID and highlight the association of increased circulating T F H with AI and GD manifestations.

Effective host defense against tuberculosis requires Th1 cytokine responses. We studied the regulation of interferon (IFN)-γ production during tuberculosis by investigating the role of CD31, a receptor that attenuates T cell receptor signals. After antigen stimulation, CD3+CD31+ blood lymphocytes decreased in healthy donors and in tuberculosis patients with robust Th1 responses to Mycobacterium tuberculosis and IFN-γ was secreted only by CD31- T cells. In contrast, in patients with weak Th1 cytokine responses to M. tuberculosis, the level of CD3+CD31+ lymphocytes was increased and IFN-γ production was low. Furthermore, the inverse relationship between CD31 expression and IFN-γ production was in contrast to signaling lymphocytic activation molecule (SLAM) expression, an IFN-γ inducer in tuberculosis. Interestingly, CD31 bound to SLAM-associated protein (SAP), an IFN-γ inhibitor in tuberculosis, and when CD31 and SAP were coexpressed in lymphocytes, their association inhibited the IFN-γ response to M. tuberculosis. Thus, CD31, when binding to SAP, interferes with Th1 responses, suggesting that CD31 has a key regulatory role in the signaling pathway(s) leading to the IFN-γ response to M. tuberculosis.

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin and mucosal edema. The main treatment goal is to enable a “normal life” for all patients. However, due to high costs, there are limited options for the management of HAE in most developing and low-income countries. As a result, most of the recommended first-line treatments are not available. In this review, we attempt to highlight the disparities in health-care resources for the management of patients with HAE amongst different countries. Data was collected from HAE experts in countries who provide tabulated information regarding management and availability of HAE treatments in their countries. We reviewed the two most recent international HAE guidelines. Using India, the world’s second most populous country, as a paradigm for HAE management in lower-income countries, we reviewed the evidence for second-line and non-recommended practices reported by HAE experts. Results suggest significant inequities in provision of HAE services and treatments. HAE patients in low-income countries do not have access to life-saving acute drugs or recently developed highly effective prophylactic medications. Most low-income countries do not have specialized HAE services or diagnostic facilities, resulting in consequent long delays in diagnosis. Suggestions for optimizing the use of limited resources as a basis for future discussion and reaching a global consensus are provided. There is an urgent need to improve HAE services, diagnostics and treatments currently available to lower-income countries. We recommend that all HAE stakeholders support the need for global equity and access to these essential measures.

Production of IFN‐γ contributes to host defense against Mycobacterium tuberculosis (Mtb) infection. We previously demonstrated that Signaling lymphocytic activation molecule‐associated protein (SAP) expression on cells from tuberculosis (TB) patients was inversely correlated with IFN‐γ production. Here we first investigated the role of NK, T‐ and B‐cell antigen (NTB‐A)/SAP pathway in the regulation of Th1 response against Mtb. Upon antigen stimulation, NTB‐A phosphorylation rapidly increases and afterwards modulates IFN‐γ and IL‐17 secretion. To sustain a healthy immune system, controlled expansion and contraction of lymphocytes, both during and after an adaptive immune response, is essential. Besides, restimulation‐induced cell death (RICD) results in an essential homeostatic mechanism for precluding excess T‐cell accumulation and associated immunopathology during the course of certain infections. Accordingly, we found that the NTB‐A/SAP pathway was required for RICD during active tuberculosis. In low responder (LR) TB patients, impaired RICD was associated with diminished FASL levels, IL‐2 production and CD25high expression after cell‐restimulation. Interestingly, we next observed that SAP mediated the recruitment of the Src‐related kinase FYNT, only in T cells from LR TB patients that were resistant to RICD. Together, we showed that the NTB‐A/SAP pathway regulates T‐cell activation and RICD during human TB. Moreover, the NTB‐A/SAP/FYNT axis promotes polarization to an unfavorable Th2‐phenotype.

CD4+ T follicular helper cells ( T F H ) were assessed in adult patients with common variable immune deficiency (CVID) classified according to the presence of granulomatous disease (GD), autoimmunity (AI), or both GD and AI (Group I) or the absence of AI and GD (Group II). T F H lymphocytes were characterized by expression of CXCR5 and PD-1. T F H were higher (in both absolute number and percentage) in Group I than in Group II CVID patients and normal controls (N). Within CXCR5+CD4+ T cells, the percentage of PD-1 (+) was higher and that of CCR7 (+) was lower in Group I than in Group II and N. The percentages of Treg and T F H reg were similar in both CVID groups and in N. T F H responded to stimulation increasing the expression of the costimulatory molecules CD40L and ICOS as did N. After submitogenic PHA+IL-2 stimulation, intracellular expression of T F H cytokines (IL-10, IL-21) was higher than N in Group I, and IL-4 was higher than N in Group II. These results suggest that T F H are functional in CVID and highlight the association of increased circulating T F H with AI and GD manifestations.