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Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P< 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Purpose The purpose of this study was to qualitatively explore perceptions related to COVID-19 vaccination intention among African American and Latinx participants and suggest intervention strategies.Approach Ninety minute virtual focus groups (N = 8), segmented by county, race and ethnicity were conducted with stakeholders from 3 vulnerable Alabama counties.Participants Participants (N = 67) were primarily African American and Latinx, at least 19 years, and residents or stakeholders in Jefferson, Mobile, and Dallas counties.Setting Focus groups took place virtually over Zoom.Methods The semi-structured guide explored perceptions of COVID-19, with an emphasis on barriers and facilitators to vaccine uptake. Focus groups lasted approximately 90 minutes and were audio recorded, transcribed, and analyzed by a team of 3 investigators, according to the guidelines of Thematic Analysis using NVivo 12. To provide guidance in the development of interventions to decrease vaccine hesitancy, we examined how themes fit with the constructs of the Health Belief Model.Results We found that primary themes driving COVID-19 vaccine hesitancy, ordered from most to least discussed, are mistrust, fear, and lack of information. Additionally, interventions to decrease vaccine hesitancy should be multi-modal, community engaged, and provide consistent, comprehensive messages delivered by trusted sources.

The University of Alabama at Birmingham academic medical center (UAB AMC) had achieved great success and growth during the 50 years since its founding. However, the challenging and more competitive environment of the 2000s left the UAB AMC on a downward trajectory. The UAB AMC had to overcome difficult internal cultural and structural barriers that stood in the way of the transformational change needed to remain competitive. Competition rather than collaborative and strategic financial investment were the primary cultural barriers for the UAB AMC, while people were the primary structural barrier. Leadership identified 5 steps that were critical for the transformation that occurred between 2013 and 2018: alignment of leadership; creating a compelling and credible shared vision; identifying cultural and structural barriers; creating a thoughtful, data-driven intervention; and improved communication and accountability. Following these steps enabled the UAB AMC to transform its institutional structure and culture. As a result, the UAB AMC thrived, returning to substantial growth in research and clinical care. UAB AMC School of Medicine grew by $100 million in National Institutes of Health funding and moved up 10 spots in ranking. In 2018, UAB Hospital had 10 specialties ranked by U.S. News & World Report, 7 more than in 2013. This article outlines the approach taken and provides a conceptual framework for other AMCs eager to transform their structure and culture and position themselves for growth.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P< 5 × 10−8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+effector T cells. Using chromatin-accessibility profiling of CD4+T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein–protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4Aand C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4Aprotecting more strongly than C4Bin both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4Aand C4Bgenerated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

The purpose of this submission to respond to a Letter to the Editor recently submitted regarding our manuscript, “Exploring COVID-19 Vaccine Hesitancy among Stakeholders in African American and Latinx Communities in the Deep South through the Lens of the Health Belief Model” published in the American Journal of Health Promotion in February, 2022. The manuscript reported on a study that had as its purpose to qualitatively explore perceptions related to COVID-19 vaccination intention among African American and Latinx participants and suggest potential intervention strategies.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (Pcombined=2.05 × 10−9, odds ratio = 0.76−0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.

African Americans carrying two apolipoprotein L1 gene (APOL1) renal risk variants have a high risk for nephropathy. However, only a minority develops end-stage renal disease (ESRD). Hence, modifying factors likely contribute to initiation of kidney disease such as endogenous (HIV infection) or exogenous (interferon treatment) environmental modifiers. In this report, genome-wide association studies and a meta-analysis were performed to identify novel loci for nondiabetic ESRD in African Americans and to detect genetic modifiers in APOL1-associated nephropathy. Two African American cohorts were analyzed, 1749 nondiabetic ESRD cases and 1136 controls from Wake Forest and 901 lupus nephritis (LN)–ESRD cases and 520 controls with systemic lupus erythematosus but lacking nephropathy from the LN-ESRD Consortium. Association analyses adjusting for APOL1G1/G2 renal-risk variants were completed and stratified by APOL1risk genotype status. Individual genome-wide association studies and meta-analysis results of all 2650 ESRD cases and 1656 controls did not detect significant genome-wide associations with ESRD beyond APOL1. Similarly, no single nucleotide polymorphism showed significant genome-wide evidence of an interaction with APOL1risk variants. Thus, although variants with small individual effects cannot be ruled out and are likely to exist, our results suggest that APOL1-environment interactions may be of greater clinical importance in triggering nephropathy in African Americans than APOL1interactions with other single nucleotide polymorphisms.

The common FcR?, an immunoreceptor tyrosine-based activation motif (ITAM)- containing adaptor protein, associates with multiple leukocyte receptor complexes and mediates signal transduction through the ITAM in the cytoplasmic domain. The presence of multiple serine and threonine residues within this motif suggests the potential for serine/threonine phosphorylation in modulating signaling events. Single-site mutational analysis of these residues in RBL-2H3 cells indicates that each may contribute to net FcR?-mediated signaling, and mass spectrometry of WT human FcR? from receptor-stimulated cells shows consistent preferential phosphorylation of the serine residue at position 51. Immunoblot analysis, mass spectrometry, and mutational analyses showed that phosphorylation of serine 51 in the 7-residue spacer between the 2 YxxL sequences regulates FcR? signaling by inhibiting tyrosine phosphorylation at the membrane proximal Y47 position of the ITAM, but not phosphorylation at position Y58. This inhibition results in reduced Syk recruitment and activation. With in vitro kinase assays, PKC-d and PKA show preferential phosphorylation of S51. Serine/threonine phosphorylation of the FcR? ITAM, which functions as an integrator of multiple signaling elements, may explain in part the contribution of variants in PKC-d and other PKC isoforms to some autoimmune phenotypes.

Introduction:The Fc receptors (FcRs) and their interactions with immunoglobulin and innate immune opsonins, such as C-reactive protein, are key players in humoral and cellular immune responses. As the effector mechanism for some therapeutic monoclonal antibodies, and often a contributor to the pathogenesis and progression of autoimmunity, FcRs are promising targets for treating autoimmune diseases.Areas covered:This review discusses the nature of different FcRs and the various mechanisms of their involvement in initiating and modulating immunocyte functions and their biological consequences. It describes a range of current strategies in targeting FcRs and manipulating their interaction with specific ligands, while presenting the pros and cons of these approaches. This review also discusses potential new strategies including regulation of FcR expression and receptor crosstalk.Expert opinion:FcRs are appealing targets in the treatment of inflammatory autoimmune diseases. However, there are still knowledge limitations and technical challenges, the most important being a better understanding of the individual roles of each of the FcRs and enhancement of the specificity in targeting particular cell types and specific FcRs.

Objective.Little is known about the genetic etiology of systemic lupus erythematosus (SLE) in individuals of African ancestry, despite its higher prevalence and greater disease severity. Overproduction of nitric oxide (NO) and reactive oxygen species are implicated in the pathogenesis and severity of SLE, making NO synthases and other reactive intermediate-related genes biological candidates for disease susceptibility. We analyzed variation in reactive intermediate genes for association with SLE in 2 populations with African ancestry.Methods.A total of 244 single-nucleotide polymorphisms (SNP) from 53 regions were analyzed in non-Gullah African Americans (AA; 1432 cases and 1687 controls) and the genetically more homogeneous Gullah of the Sea Islands of South Carolina (133 cases and 112 controls). Single-marker, haplotype, and 2-locus interaction tests were computed for these populations.Results.The glutathione reductase gene GSR(rs2253409; p = 0.0014, OR 1.26, 95% CI 1.09–1.44) was the most significant single SNP association in AA. In the Gullah, the NADH dehydrogenase NDUFS4(rs381575; p = 0.0065, OR 2.10, 95% CI 1.23–3.59) and NO synthase gene NOS1(rs561712; p = 0.0072, OR 0.62, 95% CI 0.44–0.88) were most strongly associated with SLE. When both populations were analyzed together, GSRremained the most significant effect (rs2253409; p = 0.00072, OR 1.26, 95% CI 1.10–1.44). Haplotype and 2-locus interaction analyses also uncovered different loci in each population.Conclusion.These results suggest distinct patterns of association with SLE in African-derived populations; specific loci may be more strongly associated within select population groups.

Objective.Thrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.Methods.Our discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications.Results.In the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL)rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFRrs1801131 (OR 1.51, p = 0.01), MTHFRrs1801133 (OR 0.70, p = 0.04), FVLrs6025 (OR 2.69, p = 0.002), and FGGrs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGGrs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics.Conclusion.Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.

Serine phosphorylation of the FcγRI CY domain directs its migration to lipid rafts and its interaction with protein 4.1G, suggesting a tethering role for protein 4.1G. The high‐affinity IgG receptor (CD64, FcγRI) has several special capacities, including the receptor‐stimulated cleavage of the cell surface B cell‐activating factor of the TNF superfamily (TNFSF13B). With the use of the yeast two‐hybrid system, we and others have shown that FcγRI interacts with protein 4.1G (EPB41L2). Our mutational analyses identified two required 4.1G‐interacting regions in the FcγRI CY and one FcγRI‐interacting site in the C‐terminus of protein 4.1G. Herein, we explore mechanism(s) that may regulate the interaction between protein 4.1G and FcγRI CY and influence FcγRI membrane mobility and function. We show that FcγRI CY interacts with protein 4.1G in vitro and that FcγRI coimmunoprecipitates protein 4.1G in freshly isolated human PBMC. With the use of immunostaining, we show that FcγRI colocalizes with protein 4.1G in unstimulated U937 cells, in which the FcγRI CY is constitutively serine‐phosphorylated, but significant uncoupling occurs following FcγRI cross‐linking, suggesting phosphoserine‐regulated interaction. In vitro, protein 4.1G interacted preferentially with CK2‐phosphorylated FcγRI CY, and compared with WT FcγRI, a nonphosphorylatable FcγRI mutant receptor was excluded from lipid rafts, suggesting a key role for protein 4.1G in targeting phosphorylated FcγRI to rafts. These data are consistent with a phosphoserine‐dependent tethering role for protein 4.1G in maintaining FcγRI in lipid rafts and provide insight into the unique phosphoserine‐based regulation of receptor signaling by FcγRI CY.

OBJECTIVE: To investigate the role of the FcαRI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. METHODS: The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The FcαRI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. RESULTS: We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. CONCLUSION: Our data show that the FcαRI 844 A>G polymorphism is not associated with SSc or RA susceptibility.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by a loss of tolerance to self-antigens and the production of high titers of serum autoantibodies. Lupus nephritis can affect up to 74% of SLE patients, particularly those of Hispanic and African ancestries, and remains a major cause of morbidity and mortality. A genetic etiology in SLE is now well substantiated. Thanks to extensive collaborations, extraordinary progress has been made in the past few years and the number of confirmed genes predisposing to SLE has catapulted to approximately 30. Studies of other forms of genetic variation, such as copy number variants and epigenetic alterations, are emerging and promise to revolutionize our knowledge about disease mechanisms. However, to date little progress has been made on the identification of genetic factors specific to lupus nephritis. On the near horizon, two large-scale efforts, a collaborative meta-analysis of lupus nephritis based on all genome-wide association data in Caucasians and parallel scans in four other ethnicities, are poised to make fundamental discoveries in the genetics of lupus nephritis. Collectively, these findings will show that a broad array of pathways underlines the genetic heterogeneity of SLE and lupus nephritis, and provide potential avenues for the development of novel therapies.

FcαRI (CD89) is a human IgA FcR expressed on cells of myeloid lineage such as neutrophils, monocytes, tissue macrophages, eosinophils, and subpopulations of dendritic cells. FcαRI mediates cell activation through Src family kinases and downstream tyrosine‐based phosphorylation pathways. However, the role of IgA and the expression and role of its cognate receptor FcαRI (CD89) in platelet activation are undefined. In the current study, we demonstrate that human platelets express FcαRI mRNAs and proteins. Furthermore, we show that the platelet FcαRI is associated with the FcR γ‐chain, and cross‐linking of FcαRI leads to Syk phosphorylation. Clustering of FcαRI induces pre‐mRNA splicing and protein production of tissue factor and IL‐1β, suggesting novel roles for human platelet FcαRI and serum IgA in thrombosis and inflammation.

ObjectiveTo examine the clinical and genetic correlates of hemolytic anemia and its impact on damage accrual and mortality in systemic lupus erythematosus SLE patients.MethodsSLE patients American College of Rheumatology ACR criteria of Hispanic Texan or Puerto Rican, African American, and Caucasian ethnicity from the LUMINA LUpus in MInorities, NAture versus nurture cohort were studied. Hemolytic anemia was defined as anemia with reticulocytosis ACR criterion. The association between degrees of hemolytic anemia and socioeconomicdemographic, clinical, pharmacologic, immunologic, psychological, and behavioral variables was examined by univariable and multivariable proportional odds model analyses. Genetic variables FCGRand FasFas ligand polymorphisms were examined by 2 degrees of freedom test of association and CochranArmitage trend tests. The impact of hemolytic anemia on damage accrual and mortality was examined by multivariable linear and Cox regression analyses, respectively.ResultsOf 628 patients studied, 90 were women, 19 were Texan Hispanic, 16 were Puerto Rican Hispanic, 37 were African American, and 28 were Caucasian. Sixtyfive 10 patients developed hemolytic anemia at some time during the disease course, 83 at or before diagnosis. Variables independently associated with degrees of hemolytic anemia were African American ethnicity, thrombocytopenia, and the use of azathioprine. Hemolytic anemia was associated with damage accrual after adjusting for variables known to affect this outcome; however, hemolytic anemia was not associated with mortality.ConclusionThe association of hemolytic anemia with thrombocytopenia suggests a common mechanism in their pathophysiology. Hemolytic anemia is an early disease manifestation and is associated with African American ethnicity and the use of azathioprine; it appears to exert an impact on damage but not on mortality.

Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-α stimulation. Here, we show that JAB1 is a critical regulator of the TNF-α-mediated anti-apo-ptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF-α-induced apoptosis response, reduction of nuclear factor-κB activity, delayed degradation of IκB-α, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the anti-apoptotic signal on binding of TNF-α to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF-α stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF-α can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-κB and JNK in RA FLSs.

The genetic basis of systemic lupus erythematosus, a complex genetic trait, may provide important insights into autoimmune disease. Innovation in both practical and theoretical approaches will assist in accelerating the pace of discovery and our understanding of pathogenesis.

Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to arthritic cartilage degradation. Although RASFs are normally resistant to apoptosis, Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based gene therapy has been successfully used in a mouse model of arthritis. We investigated this further by treating human RASFs with nontoxic doses of the proteasome inhibitor lactacystin. Treatment induced cytosolic accumulation of p53 and enhanced the susceptibility of RASFs to apoptosis mediated by TRAIL-R2 (DR5) but not Fas. A specific role for p53 in TRAIL-R2-mediated apoptosis was indicated by the ability of p53 siRNA to significantly reduce RASF apoptosis and by the reduced apoptosis of RASFs bearing p53 mutations on treatment with anti-DR5 antibody or anti-DR5 antibody plus lactacystin. p53 immunoprecipitation followed by mass spectrometry identified a vimentin-p53 complex, an interaction that was confirmed by reciprocal vimentin-p53 immunoprecipitation and by co-immunofluorescence. Interestingly, human caspase-4 cleaved human vimentin, and blockade of caspase-4 with a chemical inhibitor or with specific siRNA significantly inhibited TRAIL-R2-mediated apoptosis of RASFs. Furthermore, blockade of caspase-4 was paralleled by persistence of a cytosolic pattern of p53 and absence of p53 translocation to the nucleus. Taken together, our findings suggest a unique role for caspase-4 in cleaving vimentin and releasing cytosolic p53 for nuclear translocation, events that may regulate the sensitivity of RASFs to receptor-mediated apoptosis.

Although the cytoplasmic domain of the human FcgammaRIa alpha-chain lacks tyrosine-based phosphorylation motifs, it modulates receptor cycling and receptor-specific cytokine production. The cytoplasmic domain of FcgammaRIa is constitutively phosphorylated, and the inhibition of dephosphorylation with okadaic acid, an inhibitor of type 1 and type 2A protein serine/threonine phosphatase, inhibits both receptor-induced activation of the early tyrosine phosphorylation cascade and receptor-specific phagocytosis. To explore the basis for these effects of the cytoplasmic domain of FcgammaRIa, we developed a series of human FcgammaRIa molecular variants, expressed in the murine macrophage cell line P388D1, and demonstrate that serine phosphorylation of the cytoplasmic domain is an important regulatory mechanism. Truncation of the cytoplasmic domain and mutation of the cytoplasmic domain serine residues to alanine abolish the okadaic acid inhibition of phagocytic function. In contrast, the serine mutants did not recapitulate the selective effects of cytoplasmic domain truncation on cytokine production. These results demonstrate for the first time a direct functional role for serine phosphorylation in the alpha-chain of FcgammaRIa and suggest that the cytoplasmic domain of FcgammaRI regulates the different functional capacities of the FcgammaRIa-receptor complex.

Although low-affinity alleles of human Fcγ receptor types IIA and IIIA (FcγRIIA and FcγRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case–control studies, the relative contribution of these genes to SLE susceptibility has not been resolved. We analyzed the distribution of alleles of FcγRIIA, FcγRIIIA, and FcγRIIIB in 126 multiplex-SLE pedigrees and FcγRIIA and FcγRIIIA in a case–control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE. We found evidence for linkage at both the FcγRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcγRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcγRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcγRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcγRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcγRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcγ receptor cluster did not reveal any significant association beyond that observed with FcγRIIIA alone. In a large case–control replication study of 438 patients with SLE and 219 controls, FcγRIIIA provided the strongest evidence of an FcγR–SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007). To our knowledge, these data are the first to demonstrate linkage and both family-based and case–control–based association of FcγRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcγRIIIA gene in the pathophysiology of this complex genetic disease.

16.8 million SARS-CoV-2 infections in the US went undiagnosed in the first 6 months of the pandemic compared to 3.5 million diagnosed infections.

Signaling molecules from the T cell receptor ζ/Fcε receptor γ (TCRζ/FcRγ) family play a critical role in the function of Fcγ receptors and the TCR and are located on human chromosome 1, where lupus susceptibility genes are located. This study was undertaken to investigate the possibility of polymorphisms and/or mutations of TCRζ in systemic lupus erythematosus (SLE). We amplified the whole coding region of TCRζ by reverse transcriptase–polymerase chain reaction (PCR) and directly sequenced the PCR products with a dye primer technique to facilitate heterozygote detection. An alternative splicing form of TCRζ, with a CAG codon (glutamine) inserted at the splice junction of exons 4 and 5, was found both in SLE and in non-SLE subjects. Both splice isoforms of TCRζ occurred in human mixed peripheral blood mononuclear cells, natural killer cells, and Jurkat T cells. In TCRζ, 2 silent and 2 missense mutations were found, but neither coding change occurred in the immunoreceptor tyrosine–activation motif. No unique mutations were found in Caucasian, African American, Hispanic, Chinese, or Japanese SLE patients living in North America. The uncommon and equal occurrence of novel single-nucleotide polymorphisms in both SLE patients and normal subjects makes it improbable that they play important roles in genetic susceptibility to SLE.

The γ/ζ-chain family of proteins mediate cell activation for multiple immunoglobulin receptors. However, the recognition that these receptors may have distinct biologic functions suggests that additional signaling elements may contribute to functional diversity. We hypothesized that the cytoplasmic domain (CY) of the ligand binding α-chain alters the biological properties of the receptor complex. Using macrophage FcγRIa as a model system, we created stable transfectants expressing a full-length or a CY deletion mutant of human FcγRIa. Both receptors functionally associate with the endogenous murine γ-chain. However, we have established that the CY of FcγRIa directly contributes to the functional properties of the receptor complex. Deletion of the FcγRIa CY leads to slower kinetics of receptor-specific phagocytosis and endocytosis as well as lower total phagocytosis despite identical levels of receptor expression. Deletion of the CY also converts the phenotype of calcium independent FcγRIa-specific phagocytosis to a calcium-dependent phenotype. Finally, deletion of the CY abrogates FcγRIa-specific secretion of interleukin-6 but does not affect production of interleukin-1β. These results demonstrate a functional role for the CY of FcγRIa and provide a general model for understanding how multiple receptors that utilize the γ-chain can generate diversity in function.

High-dose intravenous gammaglobulin (IVIgG) was given to 12 children and adults with chronic idiopathic thrombocytopenic purpura (ITP) to avoid splenectomy or because they either failed to respond to or required maintenance with high doses of steroids and/or immunosuppressives. The average platelet count increase to initial therapy was 239,500/μ1 (range 23,000–790,000). A concomitant IgG Fc receptor blockade, measured by IgG-sensitized 51Cr-labeled autologous erythrocytes, was seen in 11 of 11 patients tested, both splenectomized and not splenecto-mized, lasting 3–4 wk. Six or more months after treatment, 2 children are in remission, 2 children and 2 adults are stable requiring no therapy with platelet counts of approximately 50,000 and 30,000, respectively, 3 children require maintenance IVIgG therapy at 2–10-wk intervals, and 1 child and 2 adults have become refractory to further IVIgG. Splenectomy was not performed in 4 children. Two adults were able to discontinue daily prednisone. The 3 patients who became unresponsive to Swiss Red Cross gammaglobulin (IgSRK) therapy did so in conjunction with a markedly elevated platelet-associated IgG and IgM. Serum IgM increased an average of 103 mg/dl after the IVIgG infusions. No significant side effects were seen.

• The renal effects of aspirin and acetaminophen are minor. With a major overdose of acetaminophen, uncommonly renal failure may occur that cannot be ascribed to hepatic failure; its mechanism is unknown. Aspirin may cause a transient shedding of renal tubular cells, alterations in urate excretion, inhibition of spironolactone action, and, in certain clinical settings, a reversible decline in renal function manifested as a fall in glomerular filtration that may be accompanied by mild water, sodium, and potassium retention. Active systemic lupus erythematosus, advanced cirrhosis, and chronic renal insufficiency seem to predispose patients to the effects on renal function, and there is direct or indirect evidence in those conditions that prostaglandin synthesis is an important part of the body's attempt to preserve renal blood flow. Study of these effects has provided new insight into the way in which the kidneys may use prostaglandins to preserve renal function when it is threatened.(Arch Intern Med 1981;141:343-348)

The efficacy, toxicity, and mechanism of effect of intravenous Anti-D (Winrho) were studied in 43 Rh+patients with immune thrombocytopenia purpura (ITP) who had not undergone splenectomy and in three already splenectomized patients. The mean platelet increase for the 43 nonsplenectomized patients was 95,000/μL (median 43,000/μL). Children had greater acute platelet responses than did adults. Human immunodeficiency virus status and duration of thrombocytopenia did not affect response. Maintenance treatment was given to patients as needed: the average interval between infusions was 24 days. The three splenectomized patients had no platelet response whatsoever. Toxicity was minimal; infusions were completed in less than 5 minutes. The generally accepted mechanism of effect of Anti-D has been Fc receptor blockade by substitution of antibody-coated red blood cells for antibody-coated platelets. Evidence is presented suggesting that the effect of IV Anti-D is not limited to Fc receptor blockade, including: (1) no correlation of parameters of hemolysis with platelet increase; (2) a 48- to 72-hour delay before platelet increase; (3) a tendency of the change in monocyte Fc receptor I expression to correlate with platelet increase; and (4) increased in vitro production of antibodies to sheep red blood cells following IV Anti-D infusion.

We have recently identified a novel human B cell differentiation factor, 446-BCDF, derived from anti-CD3-stimulated peripheral blood (PB) T cells. This novel cytokine, which may act through a pertussis toxin-sensitive G_i-linked receptor, induces a 5- to 100-fold increase in immunoglobulin (Ig) secretion by SAC (0.001%, v/v)-activated PB B cells. Coculture of B cells with 446-BCDF induces a decrease in intracellular cAMP which is necessary but not sufficient to drive terminal B cell differentiation. A second signal appears to be required. We therefore measured Ca²⁺ flux in indo-1 AM-loaded PB B cells. Stimulation with 446-BCDF resulted in an immediate rise in intracellular Ca²⁺ comparable to that seen with the anti-IgM mAb HB57. Ca²⁺ appeared to be mobilized from internal stores as pretreatment with BAPTA but not EGTA inhibited the response. Ca²⁺ mobilization was critical for the induction of differentiation as BAPTA pretreatment of PB B cells completely inhibited Ig secretion without affecting cell viability. In contrast, neither SAC, rIL6, IL2, IFN-γ, nor IL4 could mobilize Ca²⁺. Pertussis toxin, a G_i and G_o protein inhibitor, was able to inhibit 446-BCDF-induced Ca²⁺ flux as well as Ig secretion. To determine whether the Ca²⁺ flux was generated in the course of inositol phosphate turnover, we measured IP₃ turnover and the translocation of PKC from cytosol to membrane. An increase in IP₃ comparable to that seen with a monoclonal anti-human IgM antibody was noted and was specifically inhibited by the 446-BCDF-specific mAb 929. Interestingly, no membrane PKC was demonstrable in either SAC- or BCDF-stimulated B cells, although PMA (50 ng/ml) could directly activate PKC. To confirm these findings functionally, B cells were stimulated with SAC and 446-BCDF in the presence of two known PKC inhibitors, staurosporin and calphostin. No inhibition of Ig secretion was detected at any concentration tested (0.39-100 nM staurosporin and 0.0625-1 μM calphostin C). These data suggest that induction of B cell differentiation is a Ca²⁺-dependent and PTX-sensitive event. Copyright 1995, 1999 Academic Press

The importance of gastrointestinal complications in systemic lupus erythematosus (SLE) has been evident since William Osier's description of gastrointestinal crises in erythema exudativum multi-forma in 1895 (46). Thirty-five to forty percent of patients with SLE develop signs or symptoms of gastrointestinal involvement during the course of their illness (6, 17, 26). Nearly 20 percent of these patients complain of abdominal pain at some point and 9.2 percent of Dubois's series of 520 patients presented with abdominal pain as their chief complaint (18). Peritonitis (8, 40, 51, 60), ulceration (36), bowel perforation (15), hemorrhage (15) and motility disturbance (6) are commonly recognized etiologies of gastrointestinal symptoms in patients with SLE. While pancreatitis is not mentioned in some reviews of gastrointestinal pathology in SLE (6, 15, 18), Pollak (51) found acute necrotizing pancreatitis in 4 of 14 patients with severe abdominal crisis, 3 of whom died. Since the first reported case by Reifen-stein (52) in 1939, pancreatitis complicating SLE has been reported in 26 patients (8, 10, 11, 14, 22, 23, 25, 27, 35, 42, 44, 51, 52, 54, 61).

Nonsteroidal anti-inflammatory drugs and corticosteroids are important elements in the therapeutic armamentarium for patients with systemic lupus. The choice of NSAID needs to be individualized, but with optimal usage NSAIDs can often be used to manage symptoms previously treated with corticosteroids. For serious disease manifestations, corticosteroids are the cornerstone of therapy. Maximization of clinical response and avoidance of side effects continue to be important management goals.

Differing roles for [Ca2+]itransients in FcγR-mediated phagocytosis have been suggested based on the observations that antibody-opsonized erythrocyte phagocytosis by human neutrophils shows a [Ca2+]idependence, while that by murine macrophages appears [Ca2+]i-independent. To explore whether this difference might reflect different receptor isoforms or different cell types, we studied the [Ca2+]idependence of receptor-initiated phagocytosis by human FcγRIIa and a panel of FcγRIIa cytoplasmic domain mutants expressed in murine P388D1 cells and by human FcγR endogenously expressed on human neutrophils and monocytes. Wild-type and point mutants of huFcγRIIa stably transfected into murine P388D1 cells have different capacities to initiate a [Ca2+]itransient, which are closely correlated with quantitative phagocytosis (r= 0.94, p< 0.0001). Phagocytosis both by huFcγRIIa in P388D1 cells and by huFcγRIIa endogenously expressed on neutrophils and blood monocytes shows [Ca2+]idependence. Phagocytosis of antibody-opsonized erythrocytes by neutrophils demonstrated greater susceptibility to [Ca2+]iquenching compared with FcγRIIa-specific internalization with E-IV.3, suggesting that the phagocytosis activating property of FcγRIIIb in neutrophils also engages a [Ca2+]i-dependent element. In contrast, phagocytosis by human FcγRIa, endogenously expressed on blood monocytes, is [Ca2+]i-independent. Despite the importance of a consensus tyrosine activation motif for both receptors, FcγRIa and FcγRIIa engage at least some distinct signaling elements to initiate phagocytosis. The recognition that both of the phagocytic receptors on murine macrophages and human FcγRIa associate with the FcεRI γ-chain, which contains a tyrosine activation motif distinct from that in the FcγRIIa cytoplasmic domain, suggests that [Ca2+]i-independent phagocytosis is a property associated with the utilization of γ-chains by FcγR.

A patient experienced a transient deterioration of renal function induced by indomethacin during recovery from idiosyncratic phenylbutazone-associated renal failure. Since both drugs inhibit prostaglandin synthesis, this patient may illustrate a unique enhancement of the more common and clinically unimportant effect of altered glomerular filtration rate induced by such drugs. The renal insufficiency per se associated with the idiosyncratic reaction to phenylbutazone may have also enhanced this patient's reaction to indomethacin. Careful observation of patients during administration of such drugs in this and other settings of acute renal failure appears warranted.(Arch Intern Med 138:1711-1712, 1978)

Allele-dependent expression of activating FcγRIIc on human B cells enhances humoral immunity.

ELECTRON-BEAM-IRRADIATED OX FASCIA When ox fascia was introduced some years ago,1,2 one of the great difficulties was its sterilization. It was impossible to remove it from animals in slaughter houses under aseptic conditions. Also it could not be heated without altering the collagen fibrils. It, therefore, had to be sterilized by chemical sterilization. It was found that an alcohol-acetone-aqueous solution of mercurochrome (Scott's solution) would do this satisfactorily. Laboratory tests showed that this solution would kill the spores of anthrax, tetanus, or gas bacillus in a comparatively short time. However, some quirk in the Federal law prevented the producers (Ethicon) from using this solution. It was then found difficult to find an adequate sterilizing solution which was not also irritant to the tissues, causing an unfavorable reaction when the material was implanted. Finally one was found which was fairly suitable, but even this solution had to be washed out

WHILE pheochromocytomata are being reported with increasing frequency, the incidence of pheochromoblastoma, the malignant form, is infrequent enough to justify reporting the present case.A 46-year-old white man was admitted to this hospital on June 4, 1954, complaining of headache and partial blindness. He had had two previous admissions to this hospital. The first was in June, 1935, for an appendectomy when his blood pressure was recorded as 120/70, and the second was in September, 1950, for a hemorrhoidectomy when his blood pressure was recorded as 130/80 on admission and 160/100 while under thiopental (Pentothal) anesthesia for a hemorrhoidectomy. He was a patient in the Union Memorial Hospital, Baltimore, in 1946 for a spinal fusion for ruptured intervertebral disc between the 4th and 5th lumbar vertebrae. His blood pressure at that time was recorded as 170/80.He was admitted to Mercy Hospital, Baltimore, on May 15, 1954, with the same

The need for better nonabsorbable nonmetallic suture material has long been felt. Either silk or cotton would be ideal except that in the presence of infection they frequently cause persistent sinus tracts which are very troublesome. Linen is more offensive in the presence of infection than silk or cotton. Nylon also causes trouble and the knots tend to slip. Tantalum and stainless steel wire do not cause trouble in the presence of infection, but they have the disadvantages that any wire suture has; patients frequently complain of sticking pain, especially if the sutures are placed close to the skin.Over a period of years we have tested experimentally many types of nonmetallic sutures to determine their behavior in the presence of infection. Marlex, when placed in an infected wound, causes no more delay in healing than if it had not been there.1,2 Wounds healed perfectly with Marlex present, in

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93, P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin.

TO THE EDITOR.— Dr Cunningham and associates, in the Archives (138:1560-1561, 1978), reported an interesting case of systemic lupus erythematosus (SLE) and transient changes in renal function, which they attribute to lupus interstitial nephritis. While this interpretation is intriguing in view of the emerging recognition of lupus interstitial renal disease,1 an alternative explanation of the patient's deteriorating condition and response to "therapy" is possible.Aspirin and other nonsteroidal antiinflammatory drugs (NSAID) may cause acute elevations of serum creatinine value and BUN level with decreased glomerular filtration rate,2.3 which may occasionally mimic incipient acute renal failure.4 These changes are rapidly reversible when the drug therapy is discontinued, but the recovery of renal function may be confused with a "therapeutic" effect of corticosteroids initiated at the time of NSAID withdrawal.2 Patients with SLE appear to be more susceptible to this effect than normal subjects, especially if there is