Case presentationA 49-year-old Caucasian man with a history of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) was evaluated for fevers, rash, and arthritis.The patient's medical history was notable for HIV (diagnosed in 1994; last CD4 count of 500 and viral load >10,000).He was not on anti-retroviral therapy for the last year due to liver function abnormalities but had no history of opportunistic infections, he was infected with HCV (viral load greater than 3.5 million, untreated), and also carried diagnoses of hypertension, insulin-dependent diabetes mellitus, paroxysmal atrial fibrillation (not on anticoagulation), depression, and a recent negative purified protein derivative test.He had no known drug allergies.His home medications included detemir, atenolol, humulin, and lisinopril.He had a 90-pack year smoking history, as well as previous alcohol and heroin abuse (which he quit in 1999).He was living with his girlfriend, and on disability.Five months prior to this evaluation the patient was hospitalized for gross hematuria, fevers to 39°C, and nonbloody diarrhea.During the hospitalization, he developed asymmetric arthritis and a petechial rash.On physical examination, his blood pressure was 170/80 mmHg, he had synovitis of both wrists, proximal interphalangeal (PIP) joints bilaterally, and the left ankle.The rash was flat, nonblanching, purpuric, and worst over his extremities, flank, and shawl area, sparing his palms and soles.His work-up was negative for cryoglobulins; rheumatoid factor (RF); antimyeloperoxidase; and antiproteinase 3 antibodies, anti-Ro (SSA) and anti-La (SSB) antibodies, anti-nuclear antibody (ANA), and anti-double-stranded DNA antibody (dsDNA; Table 1).Complement levels were normal.Hepatitis B serologies were negative.Computerized axial tomography scan (CT scan) of the abdomen and pelvis (without contrast) showed hepatosplenomegaly.Renal ultrasound was negative for hydronephrosis.He was treated with intravenous (IV) Solumedrol 60 mg every 8 h and IV fluids, with resolution of his fever, rash, and arthritis as well as return of his creatinine to his baseline level.A renal biopsy was scheduled but the patient eloped from the hospital before the renal biopsy could be performed.The patient was seen in nephrology clinic 1 month after discharge; repeat cryoglobulins were positive with 2% precipitate and he had 4 g of proteinuria on a spot urine protein to creatinine ratio.
Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell-mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting.
Abstract Two adult patients with hypogammaglobulinemia and chronic synovitis were studied. Synovial tissue and fluid were examined by histologic, virologic, and immunologic methods. The synovium lacked characteristic histologic features of rheumatoid arthritis, and B lymphocytes were absent from the synovial tissue, fluid, and peripheral blood. These 2 patients may represent a form of chronic synovitis produced in the absence of any B lymphocyte response.
The polymorphic Ia epitope recognized by monoclonal antibody 109d6 is detectable on the leukemic cells of a significantly increased number of individuals with acute myelogenous leukemia, compared with its frequency in normal healthy control individuals. In control individuals, the presence of the 109d6 epitope is closely correlated with but not identical to the DRw53 allo-specificity. However, the frequency of particular conventional Ia allodeterminants, including DRw53, is not significantly elevated in the leukemia group. Considerable evidence supports the conclusion that the high frequency of the 109d6 epitope reflects an inherited basis for susceptibility to the development of acute myelogenous leukemia and not a differentiation event occurring in the leukemic lineage. The 109d6 determinant is expressed by leukemic myeloblasts as well as by homologous normal B cells and monocytes obtained from the same individuals during remission of the leukemia. Furthermore, in healthy family members the 109d6 epitope is encoded by Ia haplotypes that are shared with the patient. Of special interest, certain of these haplotypes have combinations of the 109d6 epitope and Ia specificities not commonly seen in normal individuals; here, also, healthy family members share these haplotypes.
gammaG globulin complexed in an unusual form has been demonstrated in the serum of many patients with rheumatoid arthritis. Such complexes have been detected and isolated principally through precipitation reactions with monoclonal gammaM rheumatoid factors. These monoclonal rheumatoid factors exhibited a greater sensitivity to react with small complexes or aggregates of gamma-globulin than polyclonal rheumatoid factor from rheumatoid arthritis sera or isolated C1q. The serum complexes consisted in large part of high molecular weight but acid-dissociable 7S gammaG globulin molecules They however differed from the complexes in the joint fluid by not yielding precipitates with C1q and were not found in association with evidence of marked serum complement fixation or activation. A small number of systemic lupus erythematosus sera, primarily those forming cryoprecipitates, also gave reactions with monoclonal rheumatoid factor. Sera from patients with a variety of nonrheumatic diseases gave a low incidence of reactions. The exact nature of the complexes in the rheumatoid arthritis sera remains somewhat in doubt although gammaG rheumatoid factors appear partly involved.
In this decade we have witnessed substantive progress in solving a number of the fundamental enigmas in systemic lupus erythematosus (SLE) that thwart progress towards achieving the goal of inducing disease remission in all patients with this challenging disease. This issue of the Annals of the Rheumatic Diseases contains a paper by Zhao et al 1 , ‘Nature of T cell epitopes in lupus antigens and HLA-DR determines autoantibody initiation and diversification’, which greatly advances understanding of four critical aspects of SLE that are included among these enigmas: Why is the susceptibility to develop SLE associated with the Major Histocompatibility class II allele desinated HLA-DR3? What role does the recognition by specific T cell clones of self-peptides presented by HLA-DR3 molecules play in the process of epitope spreading that drives the progressive intensification of a seemingly inconsequential autoimmune response to become a virulent life-threatening autoimmune disease? What roles do the peptides of the diverse commensal and environmental antigens of a person’s environment play in this progressive intensification? Lastly, what events are involved in the transition from asymptomatic autoimmunity to the heterogeneous organ involvement of clinical disease? The paper addresses these questions by analysing in detail the characteristics of both the B cell and T cell immune response to Smith antigen (Sm). It especially focuses on the particular peptides recognised by the clonally specific T cell receptors (TCRs) of the T cell clones proliferating in HLA-DR3 transgenic mice during the response to immunisation by Sm, by elegantly exploiting the property of murine T cells to be readily immortalised as hybridomas.
Several intriguing findings in this paper that address …
