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Chandra Mohan

Publications and source records attributed to Chandra Mohan.

30 records · Page 2Linked to original sources
PubMed2004

Pathogenic profiles and molecular signatures of antinuclear autoantibodies rescued from NZM2410 lupus mice.

Two outstanding questions concerning antinuclear antibodies (ANAs) in lupus involve their pathogenic potential and their molecular signatures. To address these questions, a panel of 56 antinuclear and 47 nonnuclear binding monoclonal antibodies was rescued from four seropositive NZM2410 lupus mice. The monoclonals varied in their reactivity to nucleosomes, ssDNA, dsDNA, and glomerular substrate. A large fraction of the antibodies demonstrated apparent polyreactivity (to DNA, histones, and glomerular antigens) due to bound, DNase-1 sensitive nuclear antigenic bridges. Although nephrophilic immunoglobulin (Ig) M and IgG antibodies were the most pathogenic, the dsDNA-binding antibodies were modestly so; in contrast, antinucleosome antibodies were clearly not pathogenic. Compared with the nonnuclear antigen-binding monoclonal antibodies rescued from the same mice, ANAs exhibited increased utilization of VH5/7183 genes and highly cationic heavy chain (HC) CDR3 regions. Most intriguingly, the CDR3 regions of the ANAs exhibited alternating arginine/lysine peaks at H96, H98, and H100, with neutral troughs at H95, H97, and H99. To summarize, glomerular-binding anti-dsDNA antibodies appear to be the most pathogenic variety of lupus autoantibodies. The presence of an alternating charge pattern in their HC CDR3 regions appears to be a prominent hallmark of ANAs.

Amino Acid Sequence↗
PubMed2003

Molecular signatures of anti-nuclear antibodies: contributions of specific light chain residues and a novel New Zealand Black V kappa 1 germline gene.

Although the Ig H chains of anti-nuclear Abs (ANA) have been described to possess certain shared molecular signatures, it remains unclear whether the L chains of these Abs also possess distinctive molecular features. The present study examines this by generating and analyzing two comprehensive murine Ig L chain databases, one consisting of 264 monoclonal ANAs and the other consisting of 145 non-ANAs, drawn from previously published work. Importantly, clonal replicates were represented only once each, so as to minimize bias. ANAs and non-ANAs did not differ in Vkappa family or Jkappa gene usage, nor in their mutation frequencies. Interestingly, the L chains of ANAs exhibited differential usage of certain complementarity-determining region residues, arising almost entirely from the increased usage of certain Vkappa germline genes, notably, Vkappa ai4 among anti-dsDNA ANAs, Vkappa23-45 among anti-ssDNA ANAs, and Vkappa21-12 among non-ANAs. Finally, prompted by the increased prevalence of a particular Vkappa1 family sequence among ANAs, we proceeded to clone a novel New Zealand Black Vkappa1 germline gene, named bb1.1, which appears to be frequently used to encoded anti-ssDNA Abs. Collectively, these studies underline the potential contribution of particular Vkappa germline genes in promoting or thwarting DNA binding.

Animals↗
PubMed2003

Enhanced susceptibility to end-organ disease in the lupus-facilitating NZW mouse strain.

OBJECTIVE: Although the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage. METHODS: NZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit anti-glomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates. RESULTS: Although the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 x NZW)F(1) mice were as susceptible as the NZW parents, which indicates dominant NZW contributions. CONCLUSION: Collectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZW-derived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus.

Animals↗
PubMed2003

Use of a novel elution regimen reveals the dominance of polyreactive antinuclear autoantibodies in lupus kidneys.

OBJECTIVE: The autoantibody specificities that dominate the deposits in lupus kidneys remain unclear. Reasoning that previously utilized elution buffers such as acidic glycine and ammonium thiocyanate may not have been maximally effective in eluting all Ig deposits from the kidneys, this study was conducted to experiment with a stronger dissociating agent, urea-glycine. METHODS: Seven antinuclear antibody-positive, nephritic female (SWR x NZB)F(1) (SNF1) lupus mice were selected for the elution study. Deposited Ig was eluted from their kidneys using 3 different elution buffers: 0.15M glycine-HCl buffer, 1.3M ammonia thiocyanate/0.15M glycine-HCl buffer, and 5M urea/0.15M glycine-HCl buffer. All eluates were tested for specificity against a variety of nuclear and glomerular antigens. RESULTS: Compared with conventional elution buffers, the urea-based regimen eluted severalfold more IgG and IgM antinuclear antibodies from the kidneys of nephritic SNF1 lupus mice. IgG anti-double-stranded DNA (anti-dsDNA) antibodies were not only the most prevalent species in these renal deposits, they were also heavily enriched in the kidneys, relative to the corresponding serum levels. A substantial fraction of the anti-single-stranded DNA and antihistone/DNA (but not antihistone) reactivity in these eluates was due to cross-reactive anti-dsDNA antibodies. No reactivity with SSA, SSB, Sm, RNP, Jo-1, Scl-70, or ribosomal P antigens could be demonstrated in these eluates. Importantly, the urea-glycine eluates differed from the conventional eluates in having significantly greater reactivity to glomerular substrate and laminin. CONCLUSION: This novel urea-based elution provides further support for the dominance of antibodies in lupus kidneys, with strong polyreactivity to DNA and glomerular substrate.

Animals↗
PubMed2003

Genetic underpinnings of autoimmunity--lessons from studies in arthritis, diabetes, lupus and multiple sclerosis.

Autoimmunity has been studied for more than four decades, but its genetic origins have remained a mystery. The recent past has witnessed an exponential growth in our understanding of autoimmunity resulting from both forward and reverse genetic approaches. More than 40 genes have been shown to precipitate systemic autoimmunity when genetically manipulated. In addition, reverse genetic studies in various autoimmune diseases have successfully guided researchers to specific locations on the genome that are associated with disease susceptibility. Buried within these genomic intervals lies a further treasure chest of autoimmunity genes. Efforts to unmask these culprit genes have yielded the very first clues about how an elaborate cast of players may be at work to orchestrate autoimmunity.

Arthritis↗
PubMed2003

Molecular signatures of anti-nuclear antibodies--contribution of heavy chain framework residues.

It is clear that besides the CDR residues, framework residues (particularly those on FR1 and FR3) can contribute towards antigen reactivity. This study was designed to compare the immunoglobulin heavy chain FR regions of anti-nuclear antibodies (comprised of 142 anti-ssDNA, 103 anti-dsDNA and 23 anti-nucleosome Abs) with those of non-nuclear antibodies (N=165), all drawn from the GenBank. The anti-nuclear antibodies depicted residue-usage differences that reached statistical significance in their FR1 (at H1 and H29), FR2 (at H40), and FR3 (at H69, H73, H76, H80 and H87) regions. Interestingly, these residue-usage differences were intimately linked to differences in the usage frequencies of different V(H) germline genes between the different groups of antibodies; thus, whereas J558.4, J558.47, J558.m, and 7183.9 germline genes were over-utilized among the ANAs, J558.17, V130, V(H) 36-60 and VGk1a were over-represented among the non-ANAs. In conclusion, although the framework regions of ANAs exhibited distinctly different residue-usage patterns, they may simply be markers of associated germline-encoded CDR differences that appear to have been co-selected. Further studies are warranted to ascertain if any of the observed framework residue differences do actually contribute to nuclear antigen reactivity.

Amino Acid Sequence↗
PubMed2002

Genetic dissection of systemic lupus erythematosus pathogenesis: evidence for functional expression of Sle3/5 by non-T cells.

On the non-autoimmune C57BL/6 (B6) background, the chromosome 7-derived lupus susceptibility loci Sle3 and Sle5 have been shown to mediate an elevated CD4:CD8 ratio with an increase in activated CD4(+) T cells, decreased susceptibility to apoptosis, and a break in humoral tolerance. Development of subcongenic strains has subsequently shown that the elevated CD4:CD8 ratio is due to Sle3 but that both loci contribute to the development of autoantibodies. To elucidate the functional expression patterns of these loci, adoptive transfer experiments were conducted. All possible combinations of bone marrow reconstitution, including syngenic, were conducted between the congenic B6 and B6.Sle3/5 strains. It was found that the Sle3/5 locus was functionally expressed by bone marrow-derived cells, but not by host cells, and that the elevated CD4:CD8 phenotype could be reconstituted in radiation chimeras. Using Ly5-marked congenic strains and B6 host mice, additional experiments surprisingly demonstrated that the elevated CD4:CD8 ratio was neither an intrinsic property of the T cells nor of single positive thymocytes. Allotype-marked chimeras indicated that autoantibody production by B cells was also an extrinsic property, as shown by the fact that B cells without the Sle3/5 interval contributed to autoantibody production. These experiments strongly suggest that a gene within the B6.Sle3/5 interval was expressed by a bone marrow-derived, nonlymphocyte population in the thymus and periphery and was affecting T cell selection and/or survival.

Adoptive Transfer↗
PubMed2002

Genetic dissection of SLE: SLE1 and FAS impact alternate pathways leading to lymphoproliferative autoimmunity.

Genetic dissection of lupus pathogenesis in the NZM2410 strain has recently revealed that Sle1 is a potent locus that triggers the formation of IgG anti-histone/DNA antibodies, when expressed on the B6 background as a congenic interval. B6.lpr mice, in contrast, exhibit distinctly different cellular and serological phenotypes. Both strains, however, do not usually exhibit pathogenic autoantibodies, or succumb to lupus nephritis. In this study, we show that the epistatic interaction of Sle1 (in particular, Sle1/Sle1) with FAS(lpr) leads to massive lymphosplenomegaly (with elevated numbers of activated CD4 T cells, CD4(-)CD8(-) double negative (DN) T cells, and B1a cells), high levels of IgG and IgM antinuclear (including anti-ssDNA, anti-dsDNA, and anti-histone/DNA), and antiglomerular autoantibodies, histological, and clinical evidence of glomerulonephritis, and >80% mortality by 5-6 mo of age. Whereas FAS(lpr) functions as a recessive gene, Sle1 exhibits a gene dosage effect. These studies indicate that Sle1 and FAS(lpr) must be impacting alternate pathways leading to lymphoproliferative autoimmunity.

Animals↗
PubMed2002

Molecular signatures of antinuclear antibodies-contributions of heavy chain CDR residues.

A database of the Ig heavy chains of 143 anti-ssDNA, 103 anti-dsDNA and 23 anti-nucleosome antinuclear antibodies (ANAs) was constructed, with no clonal overlap, gleaning from published literature. In comparison to the Kabat database of antibodies (N>3600), ANAs (total=269) demonstrated several significant changes, particularly in the incidence of charged or polar residues, in their CDR regions. In particular, anti-dsDNA ANAs differed significantly from anti-ssDNA ANAs in having (a) more 'D' residues at H31 and more 'Y' residues at H33, in CDR1, (b) significantly different distributions of charged or polar residues at H53, H55 and H56 of CDR2, and (c) more 'R' residues at H95-H100 of CDR3. Whereas, the differences in CDR1 and CDR3 are likely to characterize anti-dsDNA ANAs encoded by all VH families, the sequence differences in CDR2 are likely to be VH family specific. Finally, among anti-dsDNA ANAs, there was an enrichment of VH1/J558 germline genes (notably, VH 45.21.1), which bear germline-encoded amino acid residues in their CDR regions that may potentially facilitate nuclear antigen binding. This ANA heavy chain database thus constitutes a useful resource for analyzing the molecular requirements for nuclear antigen reactivity.

Animals↗
PubMed2002

Paget's disease of bone in an Indian patient: genetic and environmental factors.

Epidemiologic data have shown that Paget's disease of bone is common among people of Anglo-Saxon descent, but it is believed to be rare in India and Asia. The worldwide prevalence of the disease shows pronounced geographic and ethnic heterogeneity, and can vary in populations through migration or loss of geographic isolation. The risk to an individual who changes geographic locations, however, is difficult to quantify because the specific genetic or environmental factors responsible for Paget's disease have yet to be completely determined. We describe a case of monostotic Paget's disease in a 59-year-old Asian Indian man, and consider the potential epidemiologic and etiologic influences (moving to an area of higher disease prevalence, role of genetics, viral exposures) that may have increased his risk for the disorder. The patient presented with several months of right anterior leg pain, and was found on examination to have anterior bowing of the tibia as well as warmth and an audible bruit. Radiographs of the tibia demonstrated a V-shaped lucency, enhanced trabecular pattern, and cortical thickening. Whole-body bone scan confirmed monostotic disease with expansile uptake in the tibia, and laboratory data revealed an elevated urinary collagen N-telopeptide that normalized after bisphosphonate treatment, as did his clinical symptoms. In light of the environmental factors that appear significantly to influence the development of Paget's disease, the diagnosis should be considered in patients traditionally considered at low risk for the disorder.

Journal Article↗
PubMedDate not supplied

Systemic lupus erythematosus--recent clues from congenic strains.

Systemic lupus erythematosus is a polycongenic autoimmune disease characterized by the production of antinuclear antibodies that lead to subsequent end organ damage. The study of lupus is complicated by its polycongenic origin, contributions from hormones and the environment, epistasis among susceptibility loci, suppressive modifiers, and the fact that a single susceptibility locus may encompass multiple susceptibility genes. Murine models that develop lupus spontaneously have greatly contributed to our understanding of this disease. In particular, the advent of "congenic strains" has greatly simplified the study of this complex autoimmune disease. Thus, congenic strains bearing NZB/NZW/NZM2410, BXSB, and MRL lupus susceptibility loci are steadily replacing the traditionally studied murine lupus models as the models of choice for research. This review summarizes how researchers have used congenic strains over the past few years to dissect out and reconstruct the individual elements contributing to lupus pathogenesis.

Animals↗