Rationale for targeting complement in COVID-19.

A novel coronavirus, SARS-CoV-2, has recently emerged in China and spread internationally, posing a health emergency to the global community. COVID-19 caused by SARS-CoV-2 is associated with an acute respiratory illness that varies from mild to the life-threatening acute respiratory distress syndrome (ARDS). The complement system is part of the innate immune arsenal against pathogens, in which many viruses can evade or employ to mediate cell entry. The immunopathology and acute lung injury orchestrated through the influx of pro-inflammatory macrophages and neutrophils can be directly activated by complement components to prime an overzealous cytokine storm. The manifestations of severe COVID-19 such as the ARDS, sepsis and multiorgan failure have an established relationship with activation of the complement cascade. We have collected evidence from all the current studies we are aware of on SARS-CoV-2 immunopathogenesis and the preceding literature on SARS-CoV-1 and MERS-CoV infection linking severe COVID-19 disease directly with dysfunction of the complement pathways. This information lends support for a therapeutic anti-inflammatory strategy against complement, where a number of clinically ready potential therapeutic agents are available.

A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is a painful inflammatory complication of leprosy occurring in 50% of lepromatous leprosy patients and 5-10% of borderline lepromatous patients. It is a significant cause of economic hardship, morbidity and mortality in leprosy patients. Our understanding of the causes of ENL is limited. We performed a systematic review of the published literature and critically evaluated the evidence for the role of neutrophils, immune complexes (ICs), T-cells, cytokines, and other immunological factors that could contribute to the development of ENL. Searches of the literature were performed in PubMed. Studies, independent of published date, using samples from patients with ENL were included. The search revealed more than 20,000 articles of which 146 eligible studies were included in this systematic review. The studies demonstrate that ENL may be associated with a neutrophilic infiltrate, but it is not clear whether it is an IC-mediated process or that the presence of ICs is an epiphenomenon. Increased levels of tumor necrosis factor-α and other pro-inflammatory cytokines support the role of this cytokine in the inflammatory phase of ENL but not necessarily the initiation. T-cell subsets appear to be important in ENL since multiple studies report an increased CD4+/CD8+ ratio in both skin and peripheral blood of patients with ENL. Microarray data have identified new molecules and whole pathophysiological pathways associated with ENL and provides new insights into the pathogenesis of ENL. Studies of ENL are often difficult to compare due to a lack of case definitions, treatment status, and timing of sampling as well as the use of different laboratory techniques. A standardized approach to some of these issues would be useful. ENL appears to be a complex interaction of various aspects of the immune system. Rigorous clinical descriptions of well-defined cohorts of patients and a systems biology approach using available technologies such as genomics, epigenomics, transcriptomics, and proteomics could yield greater understanding of the condition.

Mycobacterium leprae Activates Toll-Like Receptor-4 Signaling and Expression on Macrophages Depending on Previous Bacillus Calmette-Guerin Vaccination.

Toll-like receptor (TLR)-1 and TLR2 have been shown to be receptors for Mycobacterium leprae (M. leprae), yet it is unclear whether M. leprae can signal through alternative TLRs. Other mycobacterial species possess ligands for TLR4 and genetic association studies in human populations suggest that people with TLR4 polymorphisms may be protected against leprosy. Using human embryonic kidney (HEK)-293 cells co-transfected with TLR4, we demonstrate that M. leprae activates TLR4. We used human macrophages to show that M. leprae stimulation of cytokine production is diminished if pre-treated with TLR4 neutralizing antibody. TLR4 protein expression was up-regulated on macrophages derived from non-bacillus Calmette-Guerin (BCG) vaccinated healthy volunteers after incubation with M. leprae, whereas it was down-regulated in macrophages derived from BCG-vaccinated donors. Finally, pre-treatment of macrophages derived from BCG-naive donors with BCG reversed the effect of M. leprae on TLR4 expression. This may be a newly described phenomenon by which BCG vaccination stimulates "non-specific" protection to the human immune system.

New findings in the pathogenesis of leprosy and implications for the management of leprosy.

PURPOSE OF REVIEW: This review focuses on recent work in leprosy pathogenesis. New research of both innate and adaptive immune responses to Mycobacterium leprae is described. The proposition that Mycobacterium lepromatosis is a new species causing leprosy is discussed. RECENT FINDINGS: Modulation of the lipid metabolism and reprogramming of adult Schwann cells have both been suggested as mechanisms used by M. leprae to disseminate the disease. New markers associated with localized, disseminated disease or the occurrences of leprosy reactions include the human interferons, CD163, microRNA-21, NOD2, galectin-3 and toll-like receptor 4. The role of keratinocytes instead of macrophages is underlined in the pathogenesis of leprosy. Adaptive immunity reports focus on the role of T regulatory cells and cytokines secreted by T helper cells in leprosy. Finally, a newly identified species named M. lepromatosis has been detected in patients with leprosy and severe erythema nodosum leprosum. SUMMARY: Novel biological pathways have been identified to be associated with the clinical phenotype of leprosy or the occurrence of leprosy reactions. Future work should include larger numbers of clinical samples from across the leprosy spectrum in order to give new insights in the pathogenesis and management of the disease.

Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis.

The glutathione S-transferase (GST) gene superfamily encodes for enzymes involved in conjugation of electrophilic compounds to glutathione. Several polymorphisms in the GST genes have been implicated as risk factors for prostate cancer. We did a meta-analysis of 11 studies with GSTM1 genotyping (2,063 prostate cancer cases and 2,625 controls), 10 studies with GSTT1 genotyping (1,965 cases and 2,554 controls), and 12 studies with GSTP1 genotyping (2,528 cases and 3,076 controls). The random effects odds ratio was 1.08 [95% confidence interval (95% CI), 0.93-1.25, no significant between-study heterogeneity] for the GSTM1 null versus nondeleted genotype and 0.90 (95% CI, 0.73-1.12; P = 0.03 for heterogeneity) for the GSTT1 null versus nondeleted genotype. Overall, the random effects odds ratio was 1.05 (95% CI, 0.90-1.21; P < 0.01 for heterogeneity) for the GSTP1-Val versus GSTP1-Ile allele. For all three polymorphisms, there was a trend for the presence of an association in the earliest published studies, but this did not seem to be validated in subsequent research. For GSTT1, larger studies gave different results than smaller ones. The meta-analysis shows that these three polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.

Meta-analysis of the association of the cathepsin D Ala224Val gene polymorphism with the risk of Alzheimer's disease: a HuGE gene-disease association review.

A C-to-T polymorphism in exon 2 of the cathepsin D gene encoding cathepsin D (CTSD) has been implicated as a risk factor for Alzheimer's disease. The authors performed a meta-analysis of 14 studies (16 comparisons) with CTSD genotyping (3,174 Alzheimer's disease cases and 3,298 controls). Overall, the random effects odds ratio for the T versus the C allele was 1.17 (95% confidence interval (CI): 0.95, 1.44), with some between-study heterogeneity (p < 0.01). There was significant between-study heterogeneity but no evidence of a significant association when the first hypothesis-generating study was excluded from the calculations (odds ratio (OR) = 1.11, 95% CI: 0.91, 1.35; p = 0.29). The summary odds ratio for T carriers versus T noncarriers was similar in subjects carrying or not carrying an apolipoprotein E epsilon4 allele (APOE*4). The increased susceptibility to Alzheimer's disease conferred by APOE*4 carriage tended to be more prominent in the presence of the T allele (random effects OR = 6.07, 95% CI: 4.19, 8.79, and OR = 4.09, 95% CI: 3.15, 5.31, in T carriers and noncarriers, respectively). The meta-analysis shows that the CTSD polymorphism is not a major risk factor for Alzheimer's disease, although a small effect or an enhancement of the APOE*4 effect cannot be excluded.

Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis.

Several polymorphisms in the vitamin D receptor (VDR) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 14 studies (17 comparisons) with TaqI genotyping (1870 prostate cancer cases; 2843 controls), 6 studies (8 comparisons) with poly(A) repeat genotyping (540 cases; 870 controls), 5 studies with BsmI genotyping (987 cases; 1504 controls), and 3 studies with FokI genotyping (514 cases; 545 controls). The random-effects odds ratio (OR) for the t versus T allele was 0.95 [95% confidence interval (CI), 0.86-1.05]. There was no suggestion of an overall effect either in recessive or dominant modeling, and the comparison of t/t versus T/T also showed no differential prostate cancer susceptibility (OR, 0.88; 95% CI, 0.70-1.10). No effect of t was seen in subjects of European descent (nine comparisons; OR, 0.97; 95% CI, 0.87-1.08), Asian descent (five comparisons; OR, 0.88; 95% CI, 0.66-1.17), or African descent (three comparisons; OR, 0.94; 95% CI, 0.41-2.17). There was no between-study heterogeneity in any of these analyses. Overall, the random effects OR was 0.94 (95% CI, 0.75-1.18; no between-study heterogeneity) for the S versus L allele, 0.92 (95% CI, 0.63-1.35; P < 0.01 for heterogeneity) for the B versus b allele, and 1.03 (95% CI, 0.86-1.23; no between-study heterogeneity) for the f versus F allele. The meta-analysis shows that these four polymorphisms are unlikely to be major determinants of susceptibility to prostate cancer on a wide population basis.

Molecular epidemiology of prostate cancer: androgens and polymorphisms in androgen-related genes.

In most western countries prostate cancer is the most commonly diagnosed non-skin cancer in men. Despite its high morbidity and mortality the etiology of prostate cancer remains obscure. The involvement of androgens has been examined extensively in prostate carcinogenesis but the results of most epidemiological studies remain inconclusive. This review focuses on current perspectives of androgen levels and polymorphisms in androgen-related genes. Racial differences in genetic polymorphisms that have a role in the biosynthesis and metabolism of androgens may partly account for racial differences in prostate cancer risk. Reasons are also given for inconsistent results in molecular epidemiological studies and insights and directions for future research are discussed. The development of a polygenic model for prostate cancer, incorporating multiple loci from the individual genes, may maximize the chance of identifying individuals with high-risk genotypes, resulting in better preventive, diagnostic, and therapeutic strategies.

SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis.

Several polymorphisms in the 5alpha-reductase type 2 (SRD5A2) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 9 studies (12 comparisons) with V89L genotyping (2558 prostate cancer cases and 3349 controls), 7 studies (8 comparisons) with A49T genotyping (1594 cases and 2137 controls), and 4 studies with TA repeat genotyping (1109 cases and 1378 controls). The random effects odds ratio (OR) for the L versus V allele was 1.02 [95% confidence interval (CI), 0.94-1.11]. There was no suggestion of an overall effect either in recessive or dominant modeling, and comparison of L/L versus V/V also showed no differential prostate cancer susceptibility (OR, 1.03; 95% CI, 0.83-1.28). The random effects OR for the T versus A allele was 1.56 (95% CI, 0.93-2.62). However, excluding the first published study there was no evidence for any effect (OR, 1.08; 95% CI, 0.72-1.61). Moreover, the T allele had a low prevalence (0%, 1%, and 2% in Asian, African and European controls, respectively). The random effects OR for longer versus short TA alleles was 0.88 (95% CI, 0.74-1.05). Longer TA allele homozygotes were nonsignificantly under-represented among prostate cancer cases (OR, 0.53; 95% CI, 0.26-1.06). We exclude a role for the V89L polymorphism in conferring susceptibility to prostate cancer. The A49T and TA repeat polymorphisms may have a modest effect on prostate cancer susceptibility, but bias and chance findings cannot be excluded; any genuine genetic effects would account only for a small proportion of prostate cancer in the population.

Association of the CYP17 gene polymorphism with the risk of prostate cancer: a meta-analysis.

A T-to-C polymorphism in the 5' promoter region of the CYP17 gene that encodes the cytochrome P450c17alpha has been implicated as a risk factor for prostate cancer, but individual studies have been inconclusive or controversial. Therefore we performed a meta-analysis of 10 studies (12 comparisons) with CYP17 genotyping on 2404 patients with prostate cancer and 2755 controls. Overall, the random effects odds ratio (OR) for the A2 (C) versus A1 (T) allele was 1.08 [95% confidence interval (CI), 0.95-1.22], with some between-study heterogeneity (P = 0.04). There was no suggestion of an overall effect either in recessive or dominant modeling of A2 effects, and the comparison of A2/A2 versus A1/A1 also showed no differential susceptibility to prostate cancer (OR, 1.15; 95% CI, 0.91-1.46). No effect of A2 was seen in subjects of European descent (7 comparisons, OR, 1.04; 95% CI, 0.92-1.18, no significant between-study heterogeneity) or Asian descent (2 comparisons, OR, 1.06; 95% CI, 0.66-1.71; P = 0.02 for heterogeneity), whereas A2 increased susceptibility to prostate cancer in subjects of African descent (3 comparisons, OR, 1.56; 95% CI, 1.07-2.28; no between-study heterogeneity). Smaller studies unilaterally showed more prominent genetic effects for A2 than larger studies (P = 0.038). The meta-analysis suggests that the CYP17 polymorphism is unlikely to increase considerably the risk of sporadic prostate cancer on a wide population basis, especially in subjects of European descent. Previously reported associations may reflect publication bias, although it is also possible that the polymorphism may be important in subjects of African descent.

Association between maternal and infant class I and II HLA alleles and of their concordance with the risk of perinatal HIV type 1 transmission.

We aimed to investigate the influence of class I and class II HLA specificities and of the concordance between maternal and infant HLA on vertical HIV-1 transmission. HLA typing of samples from mothers and infants enrolled in the Ariel study, a perinatal HIV-1 transmission cohort including 203 mother-infant pairs, was performed by serological and molecular methods. HLA effects were evaluated alone and by multivariate modeling considering also other known predictors of perinatal HIV-1 transmission (maternal viral load, antiretroviral therapy, duration of rupture of membranes, and histological chorioamnionitis). Modest associations were seen with specific HLA markers (increased risk with infant B67 and B58 and maternal DR1; decreased risk with maternal B12), but these were not statistically significant after adjusting for multiple comparisons. Mother-infant concordance at any class I locus was a strong predictor of transmission (odds ratio [OR], 4.16; p = 0.028). Transmission was not associated with class II concordance. Class I HLA concordance retained its importance after adjusting for maternal viral load, antiretroviral therapy, duration of rupture of membranes or histological chorioamnionitis. In multivariate modeling, only class I concordance (OR, 3.59; p = 0.069) and chorioamnionitis (OR, 3.79; p = 0.030) were retained as independent predictors of transmission. HLA alleles, and in particular the class I concordance between maternal and neonatal HLA, may regulate the risk of perinatal HIV-1 transmission.