The Role of HLA in the Association between IgA Deficiency and Celiac Disease

Selective IgA deficiency (SIgAD) is the most frequent primary immune defect. Since SIgAD is not characterized by relevant infectious issues in most cases, it is often diagnosed during the diagnostic work up of several and different autoimmune disorders, which are associated with this primary immune defect. The genetic background of SIgAD is complex and three HLA haplotypes resulted to be more frequently associated with it; in detail, two of them include HLA-DQB 1 ∗ 02 allelic variants, which are essential predisposing factors to develop Celiac Disease (CD). Here, we discuss the evidence regarding the role of HLA in the etiopathogenesis of SIgAD and its association with CD. Actually, the HLA region seems to play a modest role in the genetic predisposition to SIgAD and we may speculate that the association with the HLA-DQB 1 ∗ 02 alleles (or haplotypes including them) could derive from its link with CD. Indeed, SIgAD and some related immunological alterations are likely to predispose to several autoimmune diseases (with and despite different HLA backgrounds), including CD, which is relatively common and directly associated with the HLA-DQB 1 ∗ 02 allelic variants coding the DQ2 heterodimer. Further and specific studies are needed to make final conclusions in this regard.

Immunosuppression in Malaria: Do Plasmodium falciparum Parasites Hijack the Host?

Malaria reflects not only a state of immune activation, but also a state of general immune defect or immunosuppression, of complex etiology that can last longer than the actual episode. Inhabitants of malaria-endemic regions with lifelong exposure to the parasite show an exhausted or immune regulatory profile compared to non- or minimally exposed subjects. Several studies and experiments to identify and characterize the cause of this malaria-related immunosuppression have shown that malaria suppresses humoral and cellular responses to both homologous (Plasmodium) and heterologous antigens (e.g., vaccines). However, neither the underlying mechanisms nor the relative involvement of different types of immune cells in immunosuppression during malaria is well understood. Moreover, the implication of the parasite during the different stages of the modulation of immunity has not been addressed in detail. There is growing evidence of a role of immune regulators and cellular components in malaria that may lead to immunosuppression that needs further research. In this review, we summarize the current evidence on how malaria parasites may directly and indirectly induce immunosuppression and investigate the potential role of specific cell types, effector molecules and other immunoregulatory factors.

Infectious events in patients with severe COVID-19: results of a cohort of patients with high prevalence of underlying immune defect

Background Empirical antibiotic has been considered in severe COVID-19 although little data are available regarding concomitant infections. This study aims to assess the frequency of infections, community and hospital-acquired infections, and risk factors for infections and mortality during severe COVID-19. Methods Retrospective single-center study including consecutive patients admitted to the intensive care unit (ICU) for severe COVID-19. Competing-risk analyses were used to assess cumulative risk of infections. Time-dependent Cox and fine and gray models were used to assess risk factors for infections and mortality. Propensity score matching was performed to estimate the effect of dexamethasone. Results We included 100 patients including 34 patients with underlying malignancies or organ transplantation. First infectious event was bacterial for 35 patients, and fungal for one. Cumulative incidence of infectious events was 27% [18–35] at 10 ICU-days. Prevalence of community-acquired infections was 7% [2.8–13.9]. Incidence density of hospital-acquired infections was 125 [91–200] events per 1000 ICU-days. Risk factors independently associated with hospital-acquired infections included MV. Patient’s severity and underlying malignancy were associated with mortality. Dexamethasone was associated with increased infections (36% [20–53] vs. 12% [4–20] cumulative incidence at day-10; p = 0.01). After matching, dexamethasone was associated with hospital-acquired infections (35% [18–52] vs. 13% [1–25] at 10 days, respectively, p = 0.03), except in the subset of patients requiring MV, and had no influence on mortality. Conclusions In this population of COVID-19 patients with high prevalence of underlying immune defect, a high risk of infections was noted. MV and use of steroids were independently associated with infection rate.

Robust expansion and functional maturation of human hepatoblasts by chemical strategy

Background Chemically strategies to generate hepatic cells from human pluripotent stem cells (hPSCs) for the potential clinical application have been improved. However, producing high quality and large quantities of hepatic cells remain challenging, especially in terms of step-wise efficacy and cost-effective production requires more improvements. Methods Here, we systematically evaluated chemical compounds for hepatoblast (HB) expansion and maturation to establish a robust, cost-effective, and reproducible methodology for self-renewal HBs and functional hepatocyte-like cell (HLC) production. Results The established chemical cocktail could enable HBs to proliferate nearly 3000 folds within 3 weeks with preserved bipotency. Moreover, those expanded HBs could be further efficiently differentiated into homogenous HLCs which displayed typical morphologic features and functionality as mature hepatocytes including hepatocyte identity marker expression and key functional activities such as cytochrome P450 metabolism activities and urea secretion. Importantly, the transplanted HBs in the injured liver of immune-defect mice differentiated as hepatocytes, engraft, and repopulate in the injured loci of the recipient liver. Conclusion Together, this chemical compound-based HLC generation method presents an efficient and cost-effective platform for the large-scale production of functional human hepatic cells for cell-based therapy and drug discovery application.

Robust Expansion and Functional Maturation of Human Hepatoblasts by Chemical Strategy

Background: Chemically strategies to generate hepatic cells from human pluripotent stem cells (hPSCs) for the potential clinical application have been improved. However, producing high quality and large quantities of hepatic cells remain challenging, especially in terms of step-wise efficacy and cost-effective production requires more improvements. Methods: Here, we systematically evaluated chemical compounds for hepatoblasts (HBs) expansion and maturation to establish a robust, cost-effective and reproducible methodology for self-renewal HBs and functional hepatocyte-like cells (HLCs) production. Results: The established chemical cocktail could enable HBs to proliferate nearly 3000 folds within 3 weeks with preserved bipotency. Moreover, those expanded HBs could be further efficiently differentiated into homogenous HLCs displayed typical morphologic and functionality as mature hepatocytes, including hepatocyte identity markers expression and key functional activities such as cytochrome P450 metabolism activities and urea secretion. Importantly, the transplanted HBs in injured liver of immune-defect mice differentiated as hepatocytes, engraft and repopulate in the injured loci of the recipient liver. Conclusion: Together, this chemical compound based HLCs generation method presents an efficient and cost-effective platform for the large-scale production of functional human hepatic cells for cell-based therapy and drug discovery application.

Common variable immune deficiency: case studies

Common variable immune deficiency (CVID) is one of the most common congenital immune defects encountered in clinical practice. The condition occurs equally in males and females, and most commonly in the 20- to 40-year-old age group. The diagnosis is made by documenting reduced serum concentrations of immunoglobulin G (IgG), IgA, and usually IgM, together with loss of protective antibodies. The genetics of this syndrome are complex and are still being unraveled, but the hallmarks for most patients, as with other immune defects, include acute and chronic infections of the sinopulmonary tract. However, other noninfectious autoimmune or inflammatory conditions may also occur in CVID, and indeed these may be the first and only sign that a significant immune defect is present. These manifestations include episodes of immune thrombocytopenia, autoimmune hemolytic anemia, or neutropenia, in addition to splenomegaly, generalized or worrisome lymphadenopathy, and malignancy, especially lymphoma. These issues commonly bring the patient to the attention of hematologists for both evaluation and treatment. This article discusses 3 cases in which patients with CVID had some of these presenting issues and what hematology input was required.