Evidence for Multiple Shared Antigenic Determinants within Ro60 and Other Lupus-Related Ribonucleoprotein Autoantigens in Human Autoimmune Responses

Pal, Rahul; Deshmukh, Umesh S.; Ohyama, Yukiko; Fang, Qiang; Kannapell, Carol C.; Gaskin, Felicia; Fu, Shu Man

doi:10.4049/jimmunol.175.11.7669

Cited by 13 publications

(12 citation statements)

References 47 publications

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“…Lupus appears to be characterized by excessive apoptosis as well as defective clearance of apoptotic debris, both of which would be expected to lead to the accumulation of self‐antigens and, possibly as a consequence, an enhanced susceptibility to autoimmune disease. The specific cell‐surface recognition of “late‐stage” apoptotic cells (as defined by the presence of apoptosis‐specific moieties along with demonstrated retention of plasma membrane integrity) by antibodies has been previously reported both by us 22, 23 and by other investigators 16, 24. In this study, the IgG and IgM apoptotic cell‐specific murine monoclonal antibodies generated demonstrated cross‐reactivity across several RNP autoantigens.…”

Section: Discussionsupporting

confidence: 64%

Endogenous humoral autoreactive immune responses to apoptotic cells: Effects on phagocytic uptake, chemotactic migration and antigenic spread

et al. 2008

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Enhanced cell death and deficient clearance of cellular debris are thought to contribute to increased self-antigen exposure in systemic autoimmune disease. To investigate the characteristics of early humoral autoimmune responses, six monoclonal antibodies were generated from two autoimmune prone strains of mice. All antibodies specifically bound the surface of late-stage apoptotic cells. Similar antibody reactivities were present in the sera of patients with systemic lupus erythematosus. While IgM antibodies significantly reduced the phagocytic uptake of apoptotic thymocytes, IgG antibodies enhanced uptake. Poly-reactivity was demonstrated in the recognition of ribonucleoproteins and lipids. An antibody reactive towards lysophosphatidylcholine reversed lysophosphatidylcholinemediated inhibition of LPS-induced TNF-a production and adversely affected the transmigration of phagocytes towards an apoptotic stimulus. In several instances, CDR were characterized by the accumulation of somatic mutations. Anti-idiotypic antibodies generated upon immunization bound distinct cellular moieties and self-antigens. Polyspecific, apoptotic cell-reactive autoantibodies can therefore directly impact upon the course of disease by influencing phagocytic uptake of apoptotic cells, by inducing a proinflammatory environment through neutralization of bioactive lipids, by blinding phagocytes to the presence of dying cells through the negation of lipidic chemotactic signals, and by mediating diversification of the humoral autoimmune response via the idiotypic network.

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Section: Discussionsupporting

confidence: 64%

Endogenous humoral autoreactive immune responses to apoptotic cells: Effects on phagocytic uptake, chemotactic migration and antigenic spread

et al. 2008

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“…The antibody uniquely and dominantly bound peptide 100–119 of the α subunit and peptide 100–119 of the β subunit. A similar pattern of cross‐reactivity between non‐homologous peptides has previously been documented for human monoclonal 44 and polyclonal 45 antibodies recognizing the autoantigen Ro60 and could possibly reflect the recognition of conformational epitopes; the fact that such unusual self reactivity has now been documented in two distinct autoantigenic systems indicates broader biological relevance. Further, since Hp–Hb binding does not adversely affect the interaction of the autoreactive monoclonal antibody with Hb, the fact that the region encompassed by peptide 100–119 on the α subunit appears to be a favored epitope is in line with data suggesting that a distinct region on the α subunit (amino acids 121–135) is believed to be involved in the interaction with Hp 46.…”

Section: Discussionsupporting

confidence: 64%

Serum and organ‐associated anti‐hemoglobin humoral autoreactivity: Association with anti‐Sm responses and inflammation

et al. 2010

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The release of hemoglobin (Hb) occurs in some infectious and autoimmune diseases characterized by inflammation. As levels of haptoglobin (Hp) fall, free Hb can cause pathology. Humoral autoreactivity to human Hb was demonstrated in the sera of systemic lupus erythematosus (SLE), leishmania and malaria patients. Serum anti-murine Hb antibody levels in lupus-prone mice also exhibited an age-dependent increase, with progressive organ sequestration; significant isotypic correlation was observed with antidsDNA antibodies. A suggestive link between anti-Hb and anti-Sm responses was observed: Human lupus sera expressing anti-Sm antibody reactivity preferentially contained heightened levels of anti-Hb autoantibodies, and immunization of lupus-prone mice with Sm led to enhanced anti-murine Hb reactivity. Human and murine anti-Hb monoclonal antibodies were generated, some of which were preferentially reactive toward disease-associated methemoglobin. Epitope-mapping studies revealed evidence of intramolecular cross-reactivity. One such autoantibody synergized with Hb to enhance the secretion of pro-inflammatory cytokines while eliciting the increased production of monocyte migratory signals from endothelial cells. Preferential usage of specific variable region gene segments was not observed, although somatic mutations were documented. These studies reveal that, while the etiology, specificity and sequences of anti-Hb autoreactive antibodies can vary, they occur quite frequently and can have inflammatory consequences.

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“…In addition, autoantibodies cross-reactive with multiple SLE-related autoantigens are generated. The presence of multiple cross reactive B cell epitopes among SLE-related of autoantigens has also been confirmed by human autoantibodies (31). Our data extended those by other investigators (8, 32).…”

Section: Role Of T Cells In Autoantibody Diversification In Slementioning

confidence: 87%

Pathogenesis of systemic lupus erythematosus revisited 2011: End organ resistance to damage, autoantibody initiation and diversification, and HLA-DR

Deshmukh

Gaskin

2011

Journal of Autoimmunity

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Systemic lupus erythematosus (SLE) is a multi-system disorder resulting from interaction of susceptibility genes and environmental factors. SLE has protean clinical presentations at the initial diagnosis and relapses. SLE-related autoantibodies have unique patterns of diversification to linked proteins such as the snRNP particle and the diversification takes years before clinical diagnosis. There are both clinical and experimental evidence to indicate that separate genes contribute to autoimmunity and end organ damage and these genes are independent and interactive. Among the numerous susceptibility genes, HLA-D complex is dominant. Results from the authors’ laboratories led us to postulate a unified hypothesis for SLE pathogenesis. This hypothesis states that SLE-autoantibodies are initiated by environmental T cell epitope mimics of the SLE-related autoantigens in hosts with susceptible HLA-D alleles. These autoantibodies diversify over a period of years due the accumulation of cross-reactive T cells. This process ultimately leads to the generation of organ specific autoantibodies and autoreactive effector T cells due to the polyreactive nature of T and B cell receptors from hosts with susceptibility genes to end organ damage, resulting in protean clinical presentations. This hypothesis accounts for most of the features unique to SLE and has clinical implications as to how patients should be treated.

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Evidence for Multiple Shared Antigenic Determinants within Ro60 and Other Lupus-Related Ribonucleoprotein Autoantigens in Human Autoimmune Responses

Cited by 13 publications

References 47 publications

Endogenous humoral autoreactive immune responses to apoptotic cells: Effects on phagocytic uptake, chemotactic migration and antigenic spread

Endogenous humoral autoreactive immune responses to apoptotic cells: Effects on phagocytic uptake, chemotactic migration and antigenic spread

Serum and organ‐associated anti‐hemoglobin humoral autoreactivity: Association with anti‐Sm responses and inflammation

Pathogenesis of systemic lupus erythematosus revisited 2011: End organ resistance to damage, autoantibody initiation and diversification, and HLA-DR

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