Peptides from Vh regions of antibodies to DNA activate T cell help to upregulate autoantibody synthesis.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
R R Singh
Publications and source records attributed to R R Singh.
Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity.
Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.
Amino Acid Sequence↗
The Social Development Summit and the developing countries.
Explore the source record for details and available documents.
Congresses as Topic↗
T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus.
(NZB x NZW) F1 (BWF1) mice develop spontaneous T cell autoimmunity to VH region determinants of syngeneic anti-DNA before the onset of clinical disease. In this study, we characterized the immunogenicity, MHC binding, and lymphokine secretion patterns induced by T cell determinants from the VH region of one such anti-DNA mAb (A6.1) and examined their role in the regulation of autoimmunity. Determinants were identified by proliferation of syngeneic splenic T cells from young, unprimed BWF1 mice in response to overlapping 12-mer peptides representing the entire VH region sequence. Immunization of young BWF1 mice with any of three determinants (A6H 34-45 [p34], A6H 58-69 [p58], and A6H 84-95 [p84]) elicited proliferative responses upon in vitro recall. Upon immunization with the whole A6.1 molecule, however, proliferative responses could be recalled only to the p58 peptide, defining this as immunodominant. The other two peptides (p34 and p84) elicited minimal or no proliferation and could be termed cryptic. Proliferative responses elicited by the cryptic determinants were restricted by a single class II (I-Ed for p34 and I-Au for p84), whereas the immunodominant p58 determinant was restricted by both I-Ed and I-Eu. The cryptic p34 and p84 bound strongly to I-Ed and I-Au, respectively, whereas the immunodominant p58 peptide bound poorly to I-Ed. A6H p84 elicited T cells that secreted lymphokines in a pattern consistent with a Th1-like phenotype, whereas p58 induced a Th2-like cytokine pattern. Immunization with p34 or p84, or adoptive transfer of a p84-reactive T cell line to young BWF1 mice significantly increased IgG anti-DNA levels, accelerated nephritis, and decreased survival. In conclusion, in BWF1 mice, autoreactive T cells recognizing both cryptic and dominant self-determinants on anti-DNA autoantibodies escape deletion or anergy induction. Furthermore, since these cells are spontaneously activated before the onset of clinical disease, they may be involved in the development of the autoimmune process.
Animals↗
Genital tract abnormalities and female sexual function impairment in systemic sclerosis.
OBJECTIVE: Our purpose was to determine the involvement of the female genital tract and its functional consequences on menstrual and sexual aspects in systemic sclerosis. STUDY DESIGN: Sixty women with systemic sclerosis and 23 age- and disease duration-matched women with either rheumatoid arthritis or systemic lupus erythematosus were surveyed with a comprehensive questionnaire addressing problems before and after disease onset. Fourteen systemic sclerosis patients also had gynecologic evaluations. RESULTS: Vaginal dryness (71%), ulcerations (23%), and dyspareunia (56%) were significantly more frequent in patients with systemic sclerosis after disease onset than before and also in comparison with control subjects. Vaginal tightness and constricted introitus were present in 5 of 60 systemic sclerosis patients. More than half of systemic sclerosis patients reported a decrease in the number (p = 0.04) and intensity (p = 0.02) of orgasms, compared to < 20% of control subjects. The desire and frequency of coitus and the sexual satisfaction index were impaired equally in each group. Skin tightness, reflux-heartburn, and muscle weakness adversely affected sexual relations more in systemic sclerosis than in control subjects. On gynecologic examination 5 of 11 systemic sclerosis patients had small-sized uteri, and 3 of them had early menopause at 29, 38, and 43 years. Seven of 16 (44%) women with systemic sclerosis, compared with 6% of normal women in the United States, attained natural menopause before age 45. CONCLUSIONS: Although impairment in various indexes of sexual function occurs in a number of autoimmune diseases, decreased orgasmic function appears to be limited to systemic sclerosis. Vaginal involvement and other systemic sclerosis-related systemic symptoms adversely influence sexual relations. Menstrual abnormalities, including early menopause, affect many patients. Genital tract involvement occurs in a substantial proportion. Prospective longitudinal studies are warranted.
Adult↗
Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus.
Mechanisms that initiate and maintain autoantibody (autoAb) production in individuals with autoimmune diseases like SLE are poorly understood. Inadequate suppression of autoreactive T cells and/or unusual activation of T and B cells may underlie the persistence of pathogenic autoAbs in lupus. Here, we examine the possibility that in mice with lupus, autoAb molecules may be upregulating their own production by activating self-reactive T cells via their own processed peptides; downregulation of this circuit may decrease autoAb production and delay the development of lupus. We found that before the onset of clinical disease, lupus-prone (NZB/NZW) F1 [BWF1] (but not MHC-matched nonautoimmune mice) developed spontaneous T cell autoimmunity to peptides from variable regions of heavy chains (VH) of syngeneic anti-DNA mAbs but not to peptides from the VH region of an mAb to an exogenous antigen. Tolerizing young BWF1 mice with intravenous injections of autoAb-derived determinants substantially delayed development of anti-DNA antibodies and nephritis and prolonged survival. Thus, in such an autoAb-mediated disease, the presence of autoreactive T cells against VH region determinants of autoAbs may represent an important mechanism involved in the regulation of autoimmunity. Our findings show that tolerizing such autoreactive T cells can postpone the development of an autoimmune disease like SLE.
Amino Acid Sequence↗
A syndrome of fibrosing pleuritis, pericarditis, and synovitis with infantile contractures of fingers and toes in 2 sisters: "familial fibrosing serositis".
We describe a family in which 2 sisters born to consanguineous parents developed childhood onset fibrosing pleuritis in association with constrictive pericarditis and bilateral deforming arthropathy of large and small joints of upper and lower extremities including flexion contractures of several fingers (camptodactyly) and toes. One patient also had mitral value prolapse. Histopathological examination of the synovium and pericardium revealed fibrosis, and ultrastructural study of synovium showed abundant inter and intracellular mesh of 9 nm microfibrils. We describe this distinct clinicopathological entity with pleiotropic manifestations, the common features of which appears to be the fibrosis of serous membranes. Therefore, the term "familial fibrosing serositis" is proposed for this entity.
Adolescent↗
Granulomatous submandibular lymphadenitis caused by Salmonella species in a healthy child.
Explore the source record for details and available documents.
Child↗
Comparison of pathogenic and non-pathogenic murine antibodies to DNA: antigen binding and structural characteristics.
Three pathogenic and two non-pathogenic NZB/NZW F1 mAbs to DNA were compared. Pathogenicity was defined as the ability to induce nephritis in BALB/c mice. All mAbs were IgG2a or 2b, had high avidity for double-stranded DNA and fixed complement well. All three pathogens expressed idiotype IdGN2. Mice receiving pathogenic mAbs (compared with non-pathogenic) had more glomerular IgG deposits. The unique properties of two of the pathogens were: strong homogeneous staining of Hep-2 nuclei and the ability to bind (i) nucleosomes, (ii) histone (after mAb complexed with DNA), (iii) heparan sulfate in renal basement membranes (after complexing with DNA/histone) and (iv) nuclei in vivo. Comparison of nucleotide and amino acid sequences of the V regions of heavy and light Ig chains showed use of multiple VHDJH and V kappa J kappa gene families, with representation of several anti-DNA 'families' described by others. Arginine (R) occurred in the CDR2 or CDR3 of VH chains in all pathogens; R was absent in the CDRs of VH chains of non-pathogens. Positively and negatively charged AA were more frequent in VH CDR of pathogens than of non-pathogens. We hypothesize that the tertiary structure of mAbs determined by VH CDR regions permits stronger binding to negatively charged antigens (DNA and heparan sulfate) and to positively charged molecules (histone) in pathogens compared with non-pathogens.
Amino Acid Sequence↗
Effect of D-penicillamine on lymphocyte subsets: correlation with clinical response in rheumatoid arthritis.
We studied the effects of D-penicillamine (DP) on the clinical response, immunoinflammatory parameters and the lymphocyte subsets in 46 patients with rheumatoid arthritis (RA). Patients were evaluated before the start of the drug and then at 3 and 9 months during the follow up. 38 of 46 (82.6%) patients could continue DP treatment for over 9 months, while in 8 the drug was withdrawn due to adverse effects. Improvement in the various disease activity indices of more than 50% (responders) was seen in 25 of 38 (65.8%) patients. Responders showed a significant decrease in the serum IgA and IgM at 9 months, and in IgM only at 3 months. The serum levels of C3 and C4 did not show any significant change. Serum levels of C-reactive protein and rheumatoid factor (RF) showed a significant decrease at 3 and 9 months. A significant decrease in CD3+ and CD4+ lymphocytes along with a fall in CD4+/CD8+ lymphocyte ratio was also seen in responders at 3 and 9 months, compared to the baseline. Our results suggest that DP may have immunomodulatory action in RA.
Adolescent↗
A peptide derived from an autoantibody can stimulate T cells in the (NZB x NZW)F1 mouse model of systemic lupus erythematosus.
OBJECTIVE: To assess the ability of peptides derived from anti-DNA to stimulate syngeneic T lymphocytes and influence lupus in (NZB x NZW)F1 (NZB/W) mice. METHODS: We synthesized (by Geysen pin method) overlapping 12-mer peptides recapitulating the amino acid sequence of the VH region of a nephritogenic monoclonal IgG2a anti-DNA antibody (A6.1) from an NZB/W mouse. Splenic T cells were cultured with the peptides; multiple experiments assayed 12-mer and 16-mer peptides which contained a triple-base motif (KFKGK). We immunized 20-week-old NZB/W mice with the 12-mer and evaluated them for evidence of nephritis and for quantities of antibodies in plasma and glomeruli. RESULTS: Three clusters of peptides caused proliferation of spleen cells from young, nonimmunized mice. Both the 12-mer FYNQKFKGKATL and the 16-mer GDTFYNQKFKGKATLT peptides stimulated purified T cells. The KXKXK motif occurs in 15% of murine Ig VH (NBRF protein database), compared with 100% (6 of 6) of NZB/W anti-DNA monoclonal antibody. Immunization with the 12-mer peptide increased plasma levels of IgG, anti-DNA, and immune complexes, and levels of anti-DNA in glomeruli; nephritis was accelerated. CONCLUSION: NZB/W anti-DNA contain peptide sequences in their VH regions that stimulate self-T cells. At least one motif is frequent in NZB/W anti-DNA. If some activated T cells provide help, this mechanism may contribute to sustained up-regulation of autoantibodies in murine lupus.
Amino Acid Sequence↗
Prevalence of rheumatoid arthritis in the adult Indian population.
The prevalence of rheumatoid arthritis was studied in the adult Indian population. As the first step, a house-to-house survey of a rural population near Delhi was conducted by two trained health workers. The target population comprised 44,551 adults (over 16 years old). The health workers identified the possible cases of rheumatoid arthritis (RA) using a questionnaire. These cases were then further evaluated by the authors using the 1987 revised ARA criteria for the diagnosis of RA. A response rate of 89.5% was obtained and 3393 persons were listed as possible cases of RA by the health workers. Of these, 299 satisfied the revised ARA criteria for the diagnosis of RA, giving a prevalence of 0.75%. Projected to the whole population, this would give a total of about seven million patients in India. The prevalence of RA in India is quite similar to that reported from the developed countries. It is higher than that reported from China, Indonesia, Philippines and rural Africa. These findings are in keeping with the fact that the north Indian population is genetically closer to the Caucasians than to other ethnic groups.
Adolescent↗
Analysis of clinical and laboratory profile in Indian childhood systemic lupus erythematosus and its comparison with SLE in adults.
Data on the clinical and laboratory profiles of 83 children with SLE have been analysed and compared with data on 187 adults with the disease. The clinical features of childhood SLE are similar to those seen in adults, although clinical and laboratory parameters reflect propensity to a more severe form of the disease in the juvenile age group. However, in comparison to descriptions of childhood lupus from developed countries, in India the female-to-male ratio in this age group parallels that in adults. Renal involvement is noted to be more common, whereas gastro-intestinal and haematological abnormalities are less common. Interestingly, leucopenia, lymphopenia and nephritic type of renal involvement are commonly seen in boys with SLE, but these features are non-existent in men.
Adolescent↗
Prevalence of systemic lupus erythematosus in India.
Prevalence of systemic lupus erythematosus (SLE) was studied in the northern Indian population by means of a two-pronged approach: (a) antinuclear antibody (ANA) screening of the general population by a new well-standardized finger-prick 'filter paper' technique (sensitivity and specificity: 95.4% and 86.2%, respectively); and (b) a questionnaire survey carried out primarily by trained personnel in the community (sensitivity and specificity: 100% and 68.6% respectively). The low specificity of the two methods was improved by the introduction of a step of secondary screening by the authors, thus excluding false positives. ANA screening of 52,062 individuals yielded 13 positive results, of which only two were found to be true cases of SLE after secondary screening. Questionnaire survey of 39,826 individuals similarly yielded 3393 positive results. On secondary screening, only one of these persons was found to be a case of SLE. Thus, three cases of SLE were detected in a population survey of 91,888, giving a point prevalence of 3.2 per 100,000 (95% CI = 0-6.86 per 100,000). The reported prevalence of SLE ranges from 14 to 60 per 100,000. Thus, the prevalence of SLE in India is comparatively low. Although the reasons for low prevalence are not clear, the study used highly sensitive methodology and it is therefore unlikely that SLE cases were missed. It is hypothesized that SLE is a disease of modernization and therefore its prevalence in a predominantly rural population like that of India is low.
Antibodies, Antinuclear↗
Occurrence of autoimmune diseases and relationship of autoantibody expression with HLA phenotypes in multicase rheumatoid arthritis families.
Presence of autoimmune diseases and relationship of autoantibody expression with HLA association has been studied in 44 multicase rheumatoid arthritis (RA) families of Asian Indian origin. An increased prevalence of systemic lupus erythematosus (SLE) was observed in relatives (2.3%). Although HLA-DR4 segregated preferentially with seropositivity in general, no difference was observed among seropositive versus seronegative RA. On the other hand, no HLA association was observed with ANF positivity in these families. An increased frequency of DR7 in the ANF negative and RF negative group of RA patients compared to positive groups suggests that it may act as protective element for the development of autoantibodies in RA. An increased occurrence of DR4 in relatives affected with SLE was observed. While RA segregated mostly with HLA-DR4 in these families, autoimmune thyroid disease and insulin dependent diabetes mellitus (IDDM) segregated with HLA-DR3 suggesting the involvement of at least two sets of HLA-linked autoimmunity favouring susceptibility genes in the Indian population.
Adolescent↗
Immunogenetics of familial rheumatoid arthritis: a study of 41 multicase families.
HLA haplotypes were studied in 41 unrelated families from North India with multiple cases of rheumatoid arthritis. Affected sibpairs shared parental HLA haplotypes more often than expected (chi 2 = 13.6) according to Mendelian segregation. Using the method of sibpair ratio, nonrandom segregation of parental haplotypes was observed among affected sibs. HLA-DR4 was observed in 70% of the probands while among DR4 negative probands, DR10 occurred more frequently. However no specific haplotypic association with the disease was observed in these families.
Adult↗
Survival in patients with systemic lupus erythematosus in India.
Survival in patients with systemic lupus erythematosus (SLE) in developed countries has improved considerably over the last 2 decades. In India, however, survival in patients with SLE reported 5 years ago from this tertiary referral centre was very poor. The present study was conducted to examine trends, if any, towards improvement in the survival of patients with SLE attending the same centre during the period 1981-1990. No statistically significant change in survival was noted. It appears that improvement in the survival of SLE patients would require an overall improvement in the standard of medical care in India.
Adult↗
The Swiss Lithoclast: a new device for intracorporeal lithotripsy.
Modalities available for performing intracorporeal lithotripsy include ultrasonic, electrohydraulic and laser procedures. We present our experience with a new and unique technology for performing intracorporeal lithotripsy, namely the Swiss Lithoclast. This simple and inexpensive device uses compressed air to activate a solid probe in a manner similar to that of a jackhammer. We report the use of the Lithoclast in 31 cases, consisting of 6 renal calculi approached percutaneously, 17 ureteral calculi and 8 bladder calculi. The Lithoclast successfully fragmented 94% of the calculi. There were no intraoperative or long-term complications directly related to the use of this device. We have found the Swiss Lithoclast to be a safe, effective and inexpensive means of performing intracorporeal lithotripsy for calculi located throughout the urinary tract.
Adult↗