Biomedical subjects
Publications and source records attributed to E L Greidinger.
Apoptosis has been implicated in lupus pathogenesis in at least three different ways. As antigen, apoptotic material drives autoimmune responses. As immune modulator, impaired apoptosis makes patients susceptible to developing autoimmunity. As effector mechanism, apoptosis participates in target organ injury. This review summarizes the evidence that links apoptosis to these components of lupus pathogenesis.
OBJECTIVE: To observe the order of development of anti-U1 RNP peptide antibodies in humans. METHODS: Immunoblots against Jurkat cell lysates were performed on 5,882 serum samples from 3,668 patients referred on clinical grounds for RNP antibody testing to a reference laboratory between 1989 and 1999. In patients from whom multiple samples were drawn, we determined the order in which IgG antibodies to the U1 RNP peptides A, B'/B, C, D, and 70 kd appeared. RESULTS: One hundred sixty-three patients with serial samples were identified in whom antibodies to at least one U1 RNP peptide initially were not present but later appeared. The first RNP antibodies to appear were most often directed against the 70 kd and B'/B peptides (P < 0.01). Antibodies to the A and C peptides usually developed after other RNP peptide antibodies, and antibodies to D often emerged only after immunity to multiple other U1 RNP proteins had appeared. B'/B, but not 70 kd, was a frequent early target of spreading after initial immunity to other RNP peptides. CONCLUSION: Orderly patterns of emergence of U1 RNP peptide antibodies appear to exist in humans. Two peptides, 70 kd and B'/B, show characteristics of early immunogens in the development of human RNP immunity.
STUDY OBJECTIVES: To determine whether primary pulmonary hypertension (PPH) is associated with scleroderma-like changes in nailfold capillaries. DESIGN: Blinded, prospective, case-control study. SETTING: University medical centers in Baltimore, MD. PATIENTS: Thirty-seven patients with PPH, 15 patients with scleroderma, and 13 healthy control subjects. MEASUREMENTS: Subjects underwent nailfold capillary videomicroscopy of the fourth digits of both hands. Capillary images were evaluated by two blinded, trained graders according to standardized criteria for the presence of scleroderma nailfold changes. RESULTS: The prevalence of scleroderma-associated nailfold changes in patients with PPH (1 of 37 patients) was dramatically lower than that in patients with scleroderma (9 of 15 patients; p < 0.0001). The distribution of nailfold grades for the PPH patients was indistinguishable from that of the healthy control subjects. CONCLUSION: PPH is not associated with scleroderma-like vasculopathy of nailfold capillaries.
OBJECTIVE: To examine whether autoantibody recognition of modified forms of the U1-70-kd RNP antigen correlates with manifestations of rheumatic disease. METHODS: Blinded to clinical disease manifestations, sera from 27 rheumatic disease patients with U1-70-kd antibodies were used to immunoblot control, apoptotic, and oxidatively modified HeLa cell lysates. Using densitometry, recognition of antigen fragments was quantitated. The presence or absence of 1) lupus skin disease and 2) Raynaud's phenomenon (RP) was determined for each patient by chart review. The ability of patient sera to recognize the different fragments was compared for patients with and without skin disease and with and without RP. RESULTS: Patients with lupus skin disease had higher recognition of apoptotic U1-70 kd than did patients without skin disease (mean +/- SD fragment recognition index [FRI] 1.35 +/- 0.57 versus 0.95 +/- 0.25; P < 0.024, by Student's t-test). Patients with RP had higher recognition of oxidatively modified U1-70 kd than did patients without RP (mean +/- SD FRI 0.95 +/- 0.80 versus 0.24 +/- 0.22; P < 0.048). CONCLUSION: Recognition of apoptotically and oxidatively modified forms of the U1-70-kd autoantigen are associated with distinct clinical rheumatic disease manifestations. This finding provides in vivo evidence for the hypothesis that immune recognition of modified forms of self antigens may be relevant to the pathogenesis of systemic rheumatic diseases. Understanding the antigenic modifications to which patients react may help predict the expression of rheumatic syndromes.
A defining feature of mixed connective tissue disease (MCTD) is the presence of antibodies against the U1-ribonucleoprotein (RNP) complex, but other autoantibodies in MCTD have recently been described. Research has also further elucidated the immune responses directed against U1-RNP in humans and in murine models of disease. Hypotheses implicating modified self-antigens and/or infectious agents in the pathogenesis of MCTD have been advanced. Links between the immunologic and clinical phenomena in MCTD are emerging. Longitudinal study of patients with MCTD highlights the impact of pulmonary hypertension on disease outcome.
STUDY OBJECTIVES: To determine whether African-American race is independently associated with lung disease in scleroderma. DESIGN: Retrospective review. SETTING: University medical center in Baltimore. PATIENTS: One hundred one patients with diffuse cutaneous scleroderma with available serum samples. MEASUREMENTS: Patients underwent lung function testing as part of their routine clinical care. Percent predicted values adjusted for race were calculated for FVC, single-breath carbon monoxide diffusing capacity (Dco), and FEV1. Serum samples were assayed for the presence of antibodies to topoisomerase I and RNA polymerase II. RESULTS: Scleroderma patients of African-American race had lower percent predicted values than white patients for FVC (p<0.002), Dco (p<0.0001), and FEV1 (p<0.0001). Antibodies to topoisomerase I but not antibodies to RNA polymerase II were also associated with lung function. African-American scleroderma patients were distinct from white patients in having younger age of onset and higher prevalence of antibodies to topoisomerase I. In multivariate analyses accounting for sex, age, smoking history, years of scleroderma symptoms, and RNA polymerase II antibody status, African-American race and topoisomerase I antibody status independently predicted lower lung function. CONCLUSION: African-American race and antibodies to topoisomerase I are independent risk factors for scleroderma lung disease.
ICE family proteases have been implicated as important effectors of the apoptotic pathway, perhaps acting hierarchically in a protease cascade. Using cleavage of endogenous protease substrates as probes, three distinct tiers of ICE-like activity were observed after Fas ligation in Jurkat cells. The earliest cleavage detected (30 min) was of fodrin, and produced a 150 kDa fragment. The second phase of cleavage (50 min) involved PARP, U1-70kDa and DNA-PKcs, all substrates of the CPP32-like proteases. Lamin B cleavage was observed during the third cleavage phase (90 min). Distinct inhibition profiles obtained using a panel of peptide-based inhibitors of ICE-like proteases clearly distinguished the three different cleavage phases. These studies provide evidence for a sequence of ICE-like proteolytic activity during apoptosis. The early fodrin cleavage, producing a 150 kDa fragment, identifies an ICE-like activity proximal to CPP32 in Fas-induced Jurkat cell apoptosis.
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