Seroprevalence of Anti-SARS-CoV-2 Antibodies in Benadir Region, Somalia.

Only little is known about the true extent of COVID-19 in Somalia. The study aims to assess the seroprevalence of the COVID-19 pandemics in the Benadir region using SARS-CoV-2 antibodies and estimate the number of inhabitants infected with SARS-CoV-2. Population-based cross-sectional survey was conducted to measure the seroprevalence of antibodies against SARS-CoV-2 in the Benadir region (Mogadishu city). In the study, we enrolled 2500 Mogadishu city residents aged ≥18 years who did not receive the SARS-CoV-2 vaccine. The overall seroprevalence of IgG/IgM anti-SARS-CoV-2 antibodies was 44.8%. The seropositivity in females (56.6%) was higher than in males (46.2%). The trend in seropositivity increased with age; however, the variation was only significant in the age group 38-57 with an odds ratio and p-value of 4.11 (1.475-11.47), p = 0.007. Families with >5 members (47.2%) were more likely to test positive than those with <5 members (37%). Participants who reported COVID-19 symptoms during the pandemics or who had contact with COVID-19 patients had significantly increased IgG prevalence. Participants with larger families, individuals working in the public sector, and students showed significant seropositive results. Therefore, precautionary measures should be heightened for individuals working in the public sector.

Inhibition of Fas ligand in NOD mice unmasks a protective role for IL-10 against insulitis development.

Type 1 diabetes mellitus (T1D) is an autoimmune disease caused by the destruction of pancreatic insulin-producing ß cells by autoreactive T cells early in life. Despite daily insulin injections, patients typically develop cardiovascular and other complications; and intensive efforts are being directed toward identifying therapeutic targets to prevent the disease without directly impinging on the host defense. Fas ligand (FasL) is one potential target. Fas-FasL interactions primarily regulate T-cell homeostasis, not activation. Nevertheless, spontaneous gene mutation of Fas (called lpr mutation) or FasL (called the gld mutation) prevents autoimmune diabetes in nonobese diabetic (NOD) mice, the widely used model for T1D. Furthermore, although homozygous gld mutations cause age-dependent lymphoproliferation, limiting the gld mutation to one allele (NOD-gld/+) or treating NOD-wild-type mice with FasL-neutralizing monoclonal antibody completely prevents the disease development without causing lymphoproliferation or immune suppression. Herein, we show that the heterozygous gld mutation inhibits the accumulation of diabetogenic T cells in the pancreas, without interfering with their proliferation and expansion in the draining pancreatic lymph nodes. Pancreata from NOD-gld/+ mice contained B cells that expressed CD5 and produced IL-10, which was critical for maintenance of the disease resistance because its neutralization with an IL-10 receptor-blocking monoclonal antibody allowed accumulation of CD4 T cells in the pancreas and led to insulitis development. The results provide novel insights into the pathogenesis of T1D that could have important therapeutic implications.

Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells.

BACKGROUND: The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP) T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice) or Fas ligand (gld mice) is predominated by CD4(-)CD8(-) double negative alphabeta T cells that also express B220 and generally referred to as B220+DN T cells. Despite extensive analysis, the basis of B220+DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells. METHODOLOGY AND PRINCIPAL FINDINGS: We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220+DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220+DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220+DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220+DN T cells progressively accumulate in the periphery, eventually resulting in B220+DN T cell lymphoproliferation. CONCLUSIONS/SIGNIFICANCE: The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation.

Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically.

Spontaneous mutation of Fas (lpr) or FasL (gld) completely protects nonobese diabetic mice from autoimmune diabetes but also causes massive double-negative T-cell lymphoproliferation. In this study, we used bone marrow chimeras and adoptive transfer analysis to investigate further the role of FasL in the pathogenesis of autoimmune diabetes and to determine whether gld-induced tolerance and double-negative T-cell lymphoproliferation can be uncoupled from each other. We show that FasL expressed on hematopoietic and nonhematopoietic compartments plays nonredundant roles in the pathogenesis of autoimmune diabetes. Mutation of FasL in either compartment interferes with the autoimmune process and prevents onset of diabetes, but FasL expressed in the hematopoietic compartment is the dominant regulator of T-cell homeostasis. Furthermore, pathogenesis of diabetes is dependent on normal FasL expression in both compartments, whereas only minimal FasL function is required to maintain T-cell homeostasis. Consequently, partial disruption of FasL protects from autoimmune diabetes without causing T-cell lymphoproliferation. This is demonstrated genetically in nonobese diabetic-gld/+ mice and pharmacologically by using FasL-neutralizing antibody. These results have important implications for understanding the role of the Fas pathway in pathogenesis of autoimmune diseases and for designing novel FasL-modulating therapies.

Gld mutation of Fas ligand increases the frequency and up-regulates cell survival genes in CD25+CD4+ TR cells.

The Fas pathway and regulatory T (T(R)) cells play intertwining roles in controlling T cell tolerance through deletion and suppression of autoreactive T cells. Impairment of either mechanism causes severe T cell lymphoproliferation albeit with opposing outcomes. T cell lymphoproliferation induced by defective Fas pathway does not cause overt lymphocytic infiltration but rather prevents an important set of T cell-mediated autoimmune diseases. In contrast, deficiency in T(R) cell causes fulminant autoimmunity in very early life and fatal lymphocytic infiltration. These observations suggest existence of unidirectional fail/safe mechanism that compensate for defects in the Fas pathway but not in regulatory cells. To gain insights into how animals compensate for defects in the Fas system, we analyzed the impact of generalized lymphoproliferative disease (gld) mutation on survival, function and transcription profile of CD25+CD4+ T(R) cells. Our results show that all CD4 T cells expanded in gld mice. However, CD25+CD4+ T(R) cells are disproportionately increased in the pool of CD4 T cells perhaps due to their unique apoptosis phenotype. Freshly isolated CD25+CD4+ T(R) cells, unlike CD25-CD4+ T cells, are highly sensitive to FasL-induced apoptosis in the steady state. CD25+CD4+ T(R) cells that accumulate in gld mice express similar level of Foxp3, and have suppression potency and T(R) gene expression profile as wild-type CD25+CD4+ T(R) cells. Furthermore, the transcription profile of gld CD25+CD4+ T(R) cells is characterized by differential expression of genes involved in cell survival, metabolism and innate immune responses. These results provide a strong cellular and molecular basis for understanding why impaired Fas pathway prevents an important subset of T cell-mediated autoimmune diseases.

B220+ double-negative T cells suppress polyclonal T cell activation by a Fas-independent mechanism that involves inhibition of IL-2 production.

Fas-mediated apoptosis is a key mechanism for elimination of autoreactive T cells, yet loss of function mutations in the Fas signaling pathway does not result in overt T cell-mediated autoimmunity. Furthermore, mice and humans with homozygous Fas(lpr) or Fas ligand(gld) mutations develop significant numbers of B220+ CD4- CD8- double-negative (DN) alphabeta T cells (hereafter referred to as B220+ DN T cells) of poorly understood function. In this study, we show that B220+ DN T cells, whether generated in vitro or isolated from mutant mice, can suppress the ability of activated T cells to proliferate or produce IL-2, IL-10, and IFN-gamma. B220+ DN T cells that were isolated from either lpr or gld mice were able to suppress proliferation of autologous and syngeneic CD4 T cells, showing that suppression is Fas independent. Furthermore, restoration of Fas/Fas ligand interaction did not enhance suppression. The mechanism of suppression involves inhibition of IL-2 production and its high affinity IL-2R alpha-chain (CD25). Suppression also requires cell/cell contact and TCR activation of B220+ DN T cells, but not soluble cytokines. These findings suggest that B220+ DN T cells may be involved in controlling autoreactive T cells in the absence of Fas-mediated peripheral tolerance.