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C Mohan

Publications and source records attributed to C Mohan.

At least 19 recordsLinked to original sources
PubMed2007

Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes.

The objective of this study was to investigate the prevalence and clinical significance of a spectrum of autoantibodies in systemic lupus erythematosus and incomplete lupus syndromes using a proteome microarray bearing 70 autoantigens. Microarrays containing candidate autoantigens or control proteins were printed on 16-section slides. These arrays were used to profile 93 serum samples from patients with systemic lupus erythematosus (SLE (n = 33), incomplete LE (ILE; n = 23), first-degree relatives (FDRs) of SLE patients (n = 20) and non-autoimmune controls (NC; n = 17). Data were analysed using the significance analysis of microarray (SAM) and clustering algorithms. Correlations with disease features were determined. Serum from ILE and SLE patients contained high levels of IgG autoantibodies to 50 autoantigens and IgM autoantibodies to 12 autoantigens. Elevated levels of at least one IgG autoantibody were detected in 26% of SLE and 19% of ILE samples; elevated IgM autoantibodies were present in 13% of SLE and 17% of ILE samples. IgG autoantibodies segregated into seven clusters including two specific for DNA and RNA autoantigens that were correlated with the number of lupus criteria. Three IgG autoantibody clusters specific for collagens, DNA and histones, were correlated with renal involvement. Of the four IgM autoantibody clusters, two were correlated negatively with the number of lupus criteria; none were correlated with renal disease. The IgG : IgM autoantibody ratios generally showed a stepwise increase in the groups following disease burden from NC to SLE. Insights derived from the expanded autoantibody profiling made possible with the antigen array suggest differences in autoreactivity in ILE and SLE. Determining whether the IgM aurotreactivity that predominates in ILE represents an early stage prior to IgG switching or is persistent and relatively protective will require further longitudinal studies.

Adult↗
PubMed2006

Loss of human leucocyte antigen class I and gain of class II expression are early events in carcinogenesis: clues from a study of Barrett's oesophagus.

BACKGROUND: Human leucocyte antigen (HLA) expression is altered in oesophageal carcinomas compared with normal tissue. It is unclear, however, whether this phenotype precedes malignant transformation or results as a consequence of it. AIM: To investigate HLA class I and II expression in Barrett's oesophagus and normal squamous oesophageal tissue. METHODS: Asian patients with Barrett's oesophagus (n = 64) and a control group (n = 60) with a normal oesophagus but without reflux symptoms were recruited using endoscopic and histopathological criteria. Tissue samples were stained with monoclonal antibodies specific for HLA-ABC, HLA-DR alpha chain or HLA-DP/DQ/DR, and scored semiquantitatively. The results of immunohistochemical staining were correlated with clinical and histopathological characteristics of patients. RESULTS: Marked expression of HLA-ABC was observed in 50% of Barrett's oesophagus sections as compared with 68.3% of controls (p = 0.038). HLA-DR staining was seen in 51.6% of Barrett's oesophagus samples versus 11.7% of controls (p<0.001). Expression of HLA-DP/DQ/DR was evident in 73.4% of oesophageal intestinal metaplasia tissue as opposed to 18.3% of controls (p<0.001). Importantly, a total loss of HLA-ABC and a concomitant gain of HLA-DP/DQ/DR expression were seen in 37.5% of patients with Barrett's oesophagus but in none of the controls (p<0.001). Interestingly, this phenotype was associated positively with dysplasia (adjusted p, p* = 0.031) but negatively with non-steroidal anti-inflammatory drug use (p* = 0.004). CONCLUSIONS: HLA class I expression is down regulated and class II expression is up regulated in Barrett's oesophagus. As these changes predate malignant transformation, altered major histocompatibility complex expression may be a key event in disease progression, possibly in facilitating evasion from immune surveillance.

Adult↗
PubMed2006

Quality of life in newly diagnosed patients with lung cancer in a developing country: is it important?

There are no data regarding quality of life (QoL) assessments in lung cancer in developing countries like India. Quality of life was evaluated in 76 newly diagnosed lung cancer patients by using the World Health Organization Quality of Life questionnaire in Hindi (WHOQoL-Bref) (men 87%). The mean age was 55 years (SD = 10). Cough, dyspnoea, chest pain and haemoptysis were present in 83%, 72%, 66% and 43% of patients respectively. The median duration of symptoms was 5.9 months (range 1-13). Eighty-nine per cent had non-small cell lung cancer. The median pack-years smoked was 23 (range 0.5-88). Most patients (53%) had a Karnofsky's Performance Status (KPS) of 70 and 83% had stage III or IV disease. Quality of life did not correlate with age, gender, presence or duration of symptoms, histological type, stage of disease or degree of smoking. The physical and psychological domains of QoL correlated significantly with the KPS (P = 0.001 and P = 0.01 respectively). Patients with a KPS of 80 had better physical (P < 0.001), psychological (P < 0.01) and social (P < 0.05) QoL than those with a KPS of 70. In conclusion, patients with lung cancer in a developing country like India have an unsatisfactory QoL. The Karnofsky's Performance Scale is a simple and reliable surrogate marker for assessing QoL in these patients. Larger multi-centric studies may help in providing a more comprehensive evaluation of the effect of various demographic and clinical variables on QoL in this setting.

Carcinoma, Non-Small-Cell Lung↗
PubMed2006

Environment versus genetics in autoimmunity: a geneticist's perspective.

Both environmental as well as genetic factors have been documented to contribute to autoimmunity, as is evident from the accompanying articles in this journal. This raises an important question - which of these two elements plays a more important role in the genesis of autoimmunity? This report encapsulates a geneticist's perspective on this interesting question. Though lupus is used as an example in this essay, the proposed model is envisaged to operate in other autoimmune diseases as well.

Animals↗
PubMed2005

Human leucocyte antigen determinants of susceptibility to Barrett's oesophagus in Asians--a preliminary study.

BACKGROUND: Characteristic immune profiles have been demonstrated in gastro-oesophageal reflux disease. However, the genetic basis of gastro-oesophageal reflux disease remains unclear. AIM: To investigate whether certain human leucocyte antigen genes are associated with Barrett's oesophagus. METHODS: Asian patients of Malay, Chinese and Indian descent with Barrett's oesophagus (n = 59) and those without reflux symptoms and a normal oesophagus (n =60) were recruited prospectively using endoscopic and histopathological criteria. Human leucocyte antigen class I and II typing was performed using a polymerase chain reaction sequence-specific primers method. RESULTS: The HLA-B7 allele was present in 17% (10 of 59) of patients with Barrett's oesophagus when compared with 0% (zero of 60) of controls [P = 0.0006, corrected P = 0.0171, OR = 25.67]. Subgroup analysis revealed that the HLA-B7 allele was confined almost exclusively to Indians with Barrett's oesophagus, 43% (nine of 21) vs. 0% (zero of 19) Indian controls (P = 0.0014, corrected P = 0.0406, OR = 29.64). No class II associations, protective human leucocyte antigens or extended haplotypes for disease susceptibility were identified. CONCLUSIONS: Barrett's oesophagus in Asians, particularly Indians, is strongly positively associated with HLA-B7; reinforcing a genetic component to gastro-oesophageal reflux disease. A larger sample size and different ethnic populations should be genotyped to further confirm this association and identify possible additional risk factors in the human leucocyte antigen locus.

Asian People↗
PubMed2004

Laser bronchoscopy--current status.

The majority of patients with lung cancer have advanced disease with severe endobronchial symptoms such as cough, dyspnea, and hemoptysis for which palliation is required. Laser resection of endobronchial lesions located in the trachea, mainstem or proximal lower lobe bronchi provides significant and rapid improvement in the patient's symptoms. Neodymium:yttrium-aluminium-garnet (Nd:YAG) laser is gaining popularity due to efficient photocoagulation, good penetration and excellent hemostasis. Complications are rare and can be minimized by following standardized techniques and safety guidelines. Laser resection is equally effective with the rigid and flexible bronchoscope. The future may see combinations of laser with other palliative modalities to improve the chances of a symptom-free life for lung cancer patients.

Bronchoscopes↗
PubMed2002

Dominant NZB contributions to lupus in the (SWR x NZB)F1 model.

(SWR x NZB)F1 (or SNF1) mice succumb to lupus nephritis. Analysis of NZB x SNF1 backcross mice has recently revealed the existence of four dominant SWR loci (H2 on Chr 17, Swrl-1 on Chr 1, Swrl-2 on Chr 14 and Swrl-3 on Chr 18), and two NZB loci (Nba1 and Lbw2/Sbw2, both on Chr 4) conferring lupus susceptibility. The present study focusing on a panel of 88 SWR x SNF1 backcross mice reveals the existence of five suggestive loci for antinuclear antibody formation, consisting of three dominant NZB contributions (Nba4 on Chr 5, Lbw4 on Chr 6, and Nba5 on Chr 7), and two recessive SWR contributions (Swrl-1 on Chr 1, and Swrl-4 on Chr 10). In addition, this study reveals a dominant NZB locus for GN (Nba3 on Chr 7, peak at 31 cM), and a dominant NZB locus linked to early mortality, on Chr 10 (peak at 4 cM). Collectively, these studies suggest that lupus in the SNF1 strain is the epistatic end-product of four dominant SWR loci and four dominant NZB loci. The immunological functions and molecular identities of these loci await elucidation.

Animals↗
PubMed2001

Genetic contributions of nonautoimmune SWR mice toward lupus nephritis.

(SWR x New Zealand Black (NZB))F(1) (or SNF(1)) mice succumb to lupus nephritis. Although several NZB lupus susceptibility loci have been identified in other crosses, the potential genetic contributions of SWR to lupus remain unknown. To ascertain this, a panel of 86 NZB x F(1) backcross mice was immunophenotyped and genome scanned. Linkage analysis revealed four dominant SWR susceptibility loci (H2, Swrl-1, Swrl-2, and Swrl-3) and a recessive NZB locus, Nba1. Early mortality was most strongly linked to the H2 locus on chromosome (Chr) 17 (log likelihood of the odds (LOD) = 4.59 - 5.38). Susceptibility to glomerulonephritis was linked to H2 (Chr 17, LOD = 2.37 - 2.70), Swrl-2 (Chr 14, 36 cM, LOD = 2.48 - 2.71), and Nba1 (Chr 4, 75 cM, LOD = 2.15 - 2.23). IgG antinuclear autoantibody development was linked to H2 (Chr 17, LOD = 4.92 - 5.48), Swrl-1 (Chr 1, 86 cM, colocalizing with Sle1 and Nba2, LOD = 2.89 - 2.91), and Swrl-3 (Chr 18, 14 cM, LOD = 2.07 - 2.13). For each phenotype, epistatic interaction of two to three susceptibility loci was required to attain the high penetrance levels seen in the SNF(1) strain. Although the SWR contributions H2, Swrl-1, and Swrl-2 map to loci previously mapped in other strains, often linked to very similar phenotypes, Swrl-3 appears to be a novel locus. In conclusion, lupus in the SNF(1) strain is truly polygenic, with at least four dominant contributions from the SWR strain. The immunological functions and molecular identities of these loci await elucidation.

Animals↗
PubMed2001

Anti-subnucleosome reactivities in systemic lupus erythematosus (SLE) patients and their first-degree relatives.

Antibodies specific for dsDNA appear to have different genetic origins and pathogenic consequences, compared with histone/dsDNA-specific antibodies, in a recently described murine model. The purpose of this study was to examine if this is also true in human lupus. Sera from 40 SLE families (comprising 40 probands and 153 first-degree relatives), and 45 normal adult controls were assayed for the levels of anti-dsDNA, anti-H1/dsDNA, anti-H2A/H2B/dsDNA, and anti-H3/H4/dsDNA autoantibodies by ELISA. Both the probands and the first-degree relatives exhibited significantly increased levels of antinuclear antibodies (ANA) targeting the different subnucleosomal epitopes. Importantly, probands with anti-dsDNA antibodies had a significantly higher incidence of renal disease compared with those with just anti-H2A/H2B/dsDNA antibodies, in resonance with murine studies. The frequency of anti-dsDNA and anti-H2A/H2B/DNA ANA among the first-degree relatives was 11.8% and 18.3%, respectively. Surprisingly, whereas probands with anti-dsDNA ANA had families with several seropositive members, first-degree relatives of patients with anti-H2A/H2B/DNA ANA (but not anti-dsDNA ANA) were uniformly ANA-free. These findings suggest that anti-dsDNA ANA in lupus may not only have worse disease associations, they may also have very different genetic origins, compared with anti-H2A/H2B/DNA (or anti-nucleosome) ANA.

Adolescent↗
PubMed2001

Murine lupus genetics: lessons learned.

Recent reverse genetic studies in murine lupus have taught us the following lessons: (1) Lupus is extremely polygenic; (2) A single locus may be associated with many different phenotypes; (3) What appears to be a single locus may turn out to be a cluster of loci; (4) Different loci facilitate different immunologic steps leading to lupus; (5) Epistatic interactions between loci may engender novel autoimmune phenotypes; (6) Whereas some loci may be pathogenic, others may confer disease resistance; (7) Whereas the expression of some loci is sex-dependent, the expression of others clearly is not; (8) Two or more loci may have an impact on the same phenotype; (9) Lupus susceptibility loci appear to co-cluster with other autoimmunity susceptibility loci; (10) Lupus genes are likely to be polymorphic alleles with subtle impacts, rather than outright mutations with extreme functions. In contrast, forward genetic studies have revealed that molecules that impact apoptosis, the clearance of apoptotic cells, B-cell or T-cell function, and end-organ pathology can all potentially contribute to lupus. Collectively, the loci and genes identified by these two different approaches factorize into a few distinct pathways leading to lupus. Delineating the molecular mediators of these distinct checkpoints is the challenge that lies ahead.

Animals↗
PubMed2000

Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains.

We previously produced three congenic strains carrying lupus susceptibility genes (Sle1-Sle3) from the lupus-prone NZM2410 mouse on the C57BL/6 background and characterized their component phenotypes. Sle1 mediates the loss of tolerance to nuclear antigens; Sle2 lowers the activation threshold of B cells; and Sle3 mediates a dysregulation of CD4(+) T cells. We have now created a collection of bi- and tricongenic strains with these intervals and assessed the autoimmune phenotypes they elicit in various combinations. Our results indicate that Sle1 is key for the development of fatal lupus. The combination of Sle1 with Sle2, Sle3, or the BXSB-derived autoimmune accelerating gene yaa results in the development of systemic autoimmunity with variably penetrant severe glomerulonephritis culminating in kidney failure. In contrast, two locus combinations of Sle2, Sle3, and yaa failed to mediate fatal disease. These results indicate that the loss of tolerance to chromatin mediated by Sle1 is essential for disease pathogenesis and identify the pathway occupied by Sle1 as a strategic target for therapeutic intervention in systemic lupus erythematosus. The coexpression of Sle1, Sle2, and Sle3 as a B6-triple congenic results in severe systemic autoimmunity and fully penetrant, fatal glomerulonephritis. These results demonstrate the fulfillment of the genetic equivalent of Koch's postulate, where susceptibility loci in a lupus-prone strain have been identified by a genome scan, isolated and functionally characterized by congenic dissection, and finally shown to mediate full disease expression when recombined in a normal genome.

Animals↗
PubMed1999

Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death.

Polyclonal, generalized T cell defects, as well as Ag-specific Th clones, are likely to contribute to pathology in murine lupus, but the genetic bases for these mechanisms remain unknown. Mapping studies indicate that loci on chromosomes 1 (Sle1), 4 (Sle2), 7 (Sle3), and 17 (Sle4) confer disease susceptibility in the NZM2410 lupus strain. B6.NZMc7 mice are C57BL/6 (B6) mice congenic for the NZM2410-derived chromosome 7 susceptibility interval, bearing Sle3. Compared with B6 controls, B6.NZMc7 mice exhibit elevated CD4:CD8 ratios (2.0 vs 1.34 in 1- to 3-mo-old spleens); an age-dependent accumulation of activated CD4+ T cells (33.4% vs 21.9% in 9- to 12-mo-old spleens); a more diffuse splenic architecture; and a stronger immune response to T-dependent, but not T-independent, Ags. In vitro, Sle3-bearing T cells show stronger proliferation, increased expansion of CD4+ T cells, and reduced apoptosis (with or without anti-Fas) following stimulation with anti-CD3. With age, the B cells in this strain acquire an activated phenotype. Thus, the NZM2410 allele of Sle3 appears to impact generalized T cell activation, and this may be causally related to the low grade, polyclonal serum autoantibodies seen in this strain. Epistatic interactions with other loci may be required to transform this relatively benign phenotype into overt autoimmunity, as seen in the NZM2410 strain.

Animals↗
PubMed1999

Genetic dissection of SLE pathogenesis: adoptive transfer of Sle1 mediates the loss of tolerance by bone marrow-derived B cells.

Sle1 is a potent autoimmune susceptibility locus on chromosome 1 originally identified in a genome scan of testcross progeny between the systemic lupus erythematosus-prone NZM2410 strain and C57BL/6. We subsequently produced B6.NZMc1, a congenic strain carrying the NZM2410-derived Sle1 genomic interval on the B6 background and demonstrated that Sle1 mediated the loss of tolerance to chromatin in both the B and T cell compartments. In this communication, we show by adoptive transfer experiments that the autoimmune phenotypes of Sle1 are completely reconstituted in B6 radiation chimeras receiving B6.NZMc1 bone marrow but not by the reciprocal reconstitution, demonstrating that Sle1 is functionally expressed in B cells. In additional experiments, cotransfer of mixtures of bone marrow derived from B6.NZMc1 and nonautoimmune congenic B6 mice carrying allelic T and B cell markers showed that only B cells derived from B6.NZMc1 bone marrow produced anti-chromatin autoantibodies. In contrast, increased expression of CD69 was equivalent in CD4+ T cells derived from either B6.NZMc1 or congenic B6 bone marrow, suggesting that either T cell population could be activated subsequent to loss of tolerance in the B cell compartment. These findings indicate that the expression of Sle1 in B cells is essential for the development of autoimmunity.

Adoptive Transfer↗
PubMed1999

Multiplex inheritance of component phenotypes in a murine model of lupus.

We analyzed the linkage of GN and a wide spectrum of serological phenotypes associated with systemic lupus erythematosus in a (NZM2410 x C57BL/6)F2 cross. Some phenotypes, such as glomerulonephritis (GN) and anti-chromatin IgG antibody production, were more penetrant in females, but others, such as anti-dsDNA antibody production, did not show a gender bias. These results suggest that gender bias affects only a subset of SLE-component phenotypes, and that NZM2410 can be used to dissect the genetic basis of this phenomenon. Genome scanning linked six chromosomal intervals with the expression of one or more component phenotypes. These loci included two Sle loci previously identified in an (NZM2410 x B6)F1 x NZM2410 backcross, loci identified by others in the NZB/W model. Our analysis also suggested two new intervals on chromosomes (Chrs.) 10 and 11. Detailed analysis of the segregation of different phenotypes within these intervals suggests that they encompass more than one susceptibility locus. This clustering has been a common finding in several murine polygenic traits. Each of NZM2410 susceptibility loci can be aligned with a specific genetic pathways contributing to SLE pathogenesis on the basis of the spectrum of component phenotypes expressed.

Animals↗
PubMed1999

Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies.

Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B- and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4(+) T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis. These findings lend strong support to a two-step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.

Animals↗