Genetic variants in rheumatic fever and rheumatic heart disease

Genetic association studies in rheumatic heart disease (RHD) have the potential to contribute toward our understanding of the pathogenetic mechanism, and may shed light on controversies about RHD etiology. Furthermore, genetic association studies may uncover biomarkers that can be used to identify susceptible individuals, and contribute toward developing vaccine and novel therapeutic targets. Genetic predisposition to rheumatic fever and RHD has been hypothesized by findings from familial studies and observed associations between genes located in the human leukocyte antigens on chromosome 6p21.3 and elsewhere in the genome. We sought to summarize, from published Genetic association studies in RHD, evidence on genetic variants implicated in RHD susceptibility. Using HuGENet? systematic review methods, we evaluated 66 studies reporting on 42 genes. Existing meta‐analyses of candidate gene studies suggest that TGF‐β1 [rs1800469], and IL‐1β [rs2853550] single nucleotide polymorphisms (SNPs) contribute to susceptibility to RHD, whereas the TNF‐α [rs1800629 and rs361525], TGF‐β1 [rs1800470 and rs4803457], IL‐6 [rs1800795], IL‐10 [rs1800896] were not associated with RHD. However, candidate gene studies in RF/RHD are relatively small, thus lacking statistical power to identify reliable and reproducible findings, emphasizing the need for large‐scale multicenter studies with different populations.     

Pregnancy and rheumatic disease

Summary The present paper reviews the results of recent investigations into the influence of pregnancy and sex hormones on rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Prospective patient studies have shown that pregnancy exerts a beneficial effect on the majority of RA patients, while AS patients generally have unchanged disease activity during gestation. In AS, gestational remission was confined to patients with accompanying diseases. A postpartum disease flare-up occurred commonly in both RA and AS. Blood parameters reflected mainly the biochemical changes of normal pregnancy. A decrease of circulating immune complexes has been found in RA patients remitting during pregnancy. No single serum factor or combination of serum factors responsible for gestational remission could be detected. The possible influence of ₂-pregnancy-associated globulin on disease activity in pregnant patients remains contradictory. Hormonal contraceptives have been found to be protective against the manifestation of RA in four of five studies. However, no beneficial effect of sex hormones on the symptoms of established RA and AS could be demonstrated.     

Podocyte research in rheumatic diseases

Podocytes are glomerular visceral epithelial cells, which function as molecular sieve with foot process (FT) and slit diaphragm (SD) spanning FT, not to allow high molecular weight protein to be filtrated through glomerular capillary loop. Pathological proteinuria is caused by discoordinated tertiary podocyte structure such as disappearance of FT and/or SD, and irreversible glomeular sclerosis is caused by podocyte loss due to cell death and/or detachment from capillary wall. With recent advance of nephrological research technology such as podocyte cell culture system, genetically engineered transgenic mice with podocyte-specific regulation of gene expression, podocyte-associated biomarkers, the new isolation method of glomeruli, laser capture microdissection, multiphoton imaging and extracellular flux analyzer, new findings of pathogenesis of glomerular lesions will be expected, not only in primary glomerulonephritis, but also in secondary glomerulonephritis or glomerulopathy due to rheumatic diseases.     

Advances in potential M-protein peptide-based vaccines for preventing rheumatic fever and rheumatic heart disease

Rheumatic fever (RF) and rheumatic heart disease (RHD) are postinfectious complications of an infection (or repeated infection) with the Gram-positive bacterium, Streptococcus pyogenes (also known as group A streptococcus, GAS). RF and RHD are global problems and affect many indigenous populations of developed countries and many developing countries. However, RF and RHD are only part of a larger spectrum of diseases caused by this organism. The development of a vaccine against GAS has primarily targeted the abundant cell-surface protein called the M-protein. This review focuses on different M-protein-based-subunit vaccine approaches and the different delivery technologies used to administer these vaccine candidates in preclinical studies.     

Sex ratio and rheumatic disease

Some thyroid, rheumatic and hepatic diseases consistently have high female:male ratios, but many autoimmune diseases do not. Gonadal hormones, if they play a role in determining sex ratios, likely do so through a threshold or permissive mechanism. Sex differences related to X-inactivation, imprinting, X or Y chromosome genetic modulators, and intrauterine influences, exposures, vulnerable periods, or thresholds are alternative, theoretical, explanations for sex differences of incidence.     

Superantigen-induced T cell responses in acute rheumatic fever and chronic rheumatic heart disease patients

CD4+ and CD8+ T cells from healthy donors, acute rheumatic fever (ARF) and chronic rheumatic heart disease (CRHD) patients responded variably to a superantigen from Streptococcus pyogenes--Streptococcal pyrogenic erythrogenic toxin A (SPE-A). In vitro culture of CD4+ T cells from ARF patients (CD4-ARF) with SPE-A exhibited a Th1 type of response as they produced high levels of IL-2, while CD4+ T cells from CRHD patients (CD4-RHD) secreted IL-4 and IL-10 in large amounts, i.e. Th2 type of cytokine profile. The skewing of human CD4+ T cells (in response to SPE-A stimulation) to Th1 or Th2 type reflects the role of the two subsets in a disorder with differing intensities at the two extremes of the spectrum. Moreover, the anergy induction experiments revealed that CD8-ARF and CD8-RHD undergo anergy (to different extents), whereas CD4+ T cells do not, in response to re-stimulation by SPE-A. These results initially demonstrate that both CD4+ and CD8+ T cells respond differentially to SPE-A, and hence it is an important observation with respect to the pathogenesis of ARF/CRHD. Anergy in CD8+ T cells in the presence of SPE-A in vitro goes a step further to show the clinical relevance of these cells and their possible role in suppression of the disease.