Robert Winchester

Opportunistic infections and immune deficiency in homosexual men.

A syndrome of opportunistic infections and acquired immune deficiency occurred among four previously healthy homosexual men. Fever, leukopenia, and diminished delayed hypersensitivity were accompanied by various degrees of proctitis, perianal ulcerations, and lymphadenopathy. The infectious agents included Pneumocystis carinii, Cryptococcus neoformans, Candida albicans, herpes simplex virus, and cytomegalovirus. The immune deficiency was characterized as a persistent and profound selective decrease in the function as well as number of T lymphocytes of the helper/inducer subset and a possible activation of the suppressor/cytotoxic subset. Three patients died despite aggressive anti-infective therapy.

Association of Chronic Lyme Arthritis with HLA-DR4 and HLA-DR2 Alleles

BACKGROUND AND METHODS A small percentage of patients infected with Borrelia burgdorferi have chronic Lyme arthritis that does not respond to antibiotic therapy. To learn whether genetically determined variations in the host immune response might account for such outcomes, we determined the immunogenetic profiles of 130 patients with various manifestations of Lyme disease. RESULTS Of the 80 patients with arthritis, 57 percent of those with chronic arthritis (12 to 48 months in duration) had the HLA-DR4 specificity; only 23 percent of those with arthritis of moderate duration (6 to 11 months) and only 9 percent of those with arthritis of short duration (1 to 5 months) had this specificity (P = 0.003). After the HLA-DR4-positive patients were excluded from each group, a secondary association was noted with HLA-DR2, which was found in 75 percent of the remaining patients with chronic arthritis and in 50 percent of those with arthritis of moderate duration, but in only 20 percent of those with arthritis of short duration (P = 0.023). Altogether, 25 of the 28 patients with chronic arthritis (89 percent) had HLA-DR2 or HLA-DR4, or both, as compared with 27 percent of those with arthritis of short duration (relative risk, 22; P = 0.00006). These HLA specificities appeared to act as independent, dominant markers of susceptibility. Nucleotide-sequence typing, performed in five patients with chronic arthritis, identified the HLA-DR2 allele as Dw2 (DR beta 1*1501), and the HLA-DR4 alleles as Dw4, Dw14, and Dw13 (DR beta 1*0401, DR beta 1*0404, and DR beta 1*0403, respectively). The presence of HLA-DR4 in patients with arthritis was associated with a lack of response to antibiotic therapy (P = 0.01). CONCLUSIONS Particular Class II major histocompatibility genes determine a host immune response to B. burgdorferi that results in chronic arthritis and lack of response to antibiotic therapy.

The Co-occurrence of Reiter's Syndrome and Acquired Immunodeficiency

Thirteen patients who had the co-occurrence of severe Reiters syndrome and the acquired immunodeficiency syndrome (AIDS) or its syndromes were studied. The arthritis was reactive in three patients and without defined cause in the others. Nine patients had HLA-B27. The two syndromes appeared simultaneously in four patients, suggesting a common biologic process, and in the others the immunodeficiency either preceded or followed the arthritis. Reiters syndrome occurring in the setting of this profound immunodeficiency suggests that helper T cells were not involved in the pathogenesis of the rheumatic disease. Difficulties were encountered in the diagnosis of either syndrome in the presence of the other. Two patients with Reiters syndrome developed Kaposis sarcoma and fulminant AIDS after receiving methotrexate, which emphasizes the need for caution in the use of immunosuppressive therapy in Reiters syndrome. An additional patient with undifferentiated spondylarthropathy subsequently developed psoriasis in conjunction with the onset of AIDS.

INTERLEUKIN 8 IS INDUCED BY CHOLESTEROL LOADING OF MACROPHAGES AND EXPRESSED BY MACROPHAGE FOAM CELLS IN HUMAN ATHEROMA

In order to identify novel genes expressed in macrophage-derived foam cells, we used a multigene assay to examine the expression of genes in control versus cholesterol-loaded macrophages. We compared THP-1 macrophages incubated with or without acetylated LDL (acLDL) ± acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor (compound 58035) for 20 h and assessed changes in mRNA of chemokines, growth factors, interleukins, and adhesion molecules. Among 49 genes examined, an increase in mRNA was observed only for interleukin 8 (IL-8) in THP-1 macrophages. Northern analysis confirmed a 3- to 4-fold increase of IL-8 mRNA and an enzyme-linked immunosorbent assay (ELISA) revealed a corresponding increase in IL-8 in conditioned medium. Oxidized LDL (oxLDL) also induced IL-8 mRNA, but native LDL had no effect. 58035 had a moderate effect on IL-8 induction by acLDL. AcLDL-induced IL-8 expression was concentration- and time-dependent. The time course of IL-8 induction paralleled that of cholesterol loading. MCP-1, a chemokine implicated in recruiting monocytes in atherogenesis, was also induced by acLDL. The induction of MCP-1, however, peaked at 1 h after addition of acLDL and returned to basal level by 20 h while IL-8 induction peaked at 8 h and was still 2-fold higher than basal level at 20 h. IL-8 induction was also observed in fresh human monocyte-derived macrophage cells treated with acLDL. Finally, immunohistochemistry and in situ hybridization studies using specimens of human coronary atheromas showed expression of IL-8 mRNA in a macrophage-rich area. We conclude that IL-8 is induced in macrophage foam cells as a response to cholesterol loading. The chemoattractant and/or mitogenic effects of IL-8 on neutrophils, T cells, smooth muscle, or vascular endothelial cells may contribute to the progression and complications of atherosclerosis.

A Diffuse Infiltrative CD8 Lymphocytosis Syndrome in Human Immunodeficiency Virus (HIV) Infection: A Host Immune Response Associated with HLA-DR5

STUDY OBJECTIVE To describe the clinical, immunologic, and immunogenetic features of a diffuse infiltrative lymphocytic disorder resembling Sjögren syndrome in persons infected with human immunodeficiency virus (HIV). DESIGN Clinical case study. SETTING University-affiliated hospitals and outpatient clinics. PATIENTS Consecutive sample of 17 patients. MEASUREMENTS AND MAIN RESULTS All of the 17 patients had bilateral parotid gland enlargement; 14 had xerostomia and 6 had xerophthalmia. Of the 17 patients, 14 had generalized lymphadenopathy, 10 had histologically proved lymphocytic interstitial pneumonitis, 4 had neurologic involvement, and 3 had lymphocytic infiltration of the gastrointestinal tract. Gallium scanning in all of 11 tested patients showed abnormal salivary gland uptake. Minor salivary gland biopsies showed more than 2 lymphocytic foci per 4 mm2 tissue in all of 11 tested patients, the infiltrate consisting predominantly of CD8 cells. Fifteen patients had circulating CD8 lymphocytosis; the principal phenotype of these cells was CD8+ CD29+. Rheumatoid factor and antinuclear antibodies were infrequent, and none of the patients had anti-Ro/SS-A or anti-La/SS-B antibodies. HLA-DR5 was significantly more frequent in the black patients (10 of 12) compared with controls (13 of 45). Only one patient developed an opportunistic infection during 544 patient-months of study, and none has died of AIDS. CONCLUSIONS A distinct syndrome primarily characterized by parotid gland enlargement, sicca symptoms, and pulmonary involvement occurs in HIV infection. This disorder is associated with CD8 lymphocytosis and the presence of HLA-DR5, and appears to be a genetically determined host immune response to HIV.

The Human la System

Publisher Summary This chapter discusses conceptual and technical developments in the field of human Ia antigens by describing the chemical structure and immunologic relationship to their murine counterparts. The distribution of human Ia antigens is limited primarily to the B lymphocyte series, stimulated T cells, and stem and precursor hematopoietic cells, suggestive of both cell type and differentiation specificity. The association of certain Ia antigens with susceptibility or resistance to a variety of diseases, including rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, rheumatic fever, multiple sclerosis, and diabetes, provides both a valuable clinical predictive measure and a lead for the future study of pathogenetic factors possibly related to the particular Ia genes involved. The chapter examines the Ia antigens from two principal perspectives: (1) as membrane components related to differentiation, and (2) as part of a genetically intricate system of molecules bearing alloantigens that have relevance to susceptibility to certain diseases. Three types of antisera are used to detect Ia antigens: alloantisera, heteroantisera raised in rabbits or similar species, and monoclonal hybridoma reagents. It is apparent that the relationship of diseases to the Ia alloantigens is an intricate one and is likely to involve several distinct factors.

The Molecular Basis of Susceptibility to Rheumatoid Arthritis

Publisher Summary This chapter discusses the development, current understanding, and some of the implications of the molecular basis of susceptibility to rheumatoid arthritis as it relates to the inheritance of particular polymorphic conformations of the major histocompatibility complex (MHC) class II molecules. The way the interpretation of these susceptibility structures as peptide-binding pockets alters the paradigm underlying the study of histocompatibility leukocyte antigens (HLA)-disease associations to one based on rational structural hypotheses is discussed. Disease susceptibility genes, rather than being “disease genes,” are MHC class II alleles that are positively selected and physiologic. The penetrance of rheumatoid arthritis is accordingly low, but in the heterozygous state, the gene encoding the shared epitope confers susceptibility indicating it has a dominant mode of action. However, when two susceptibility alleles are inherited together this greatly increase the penetrance and severity of the ensuing disease and raises questions about the way these structures act cooperatively to provide the molecular basis of susceptibility. From the perspective of the person with rheumatoid arthritis, the illness usually appears to be a sporadic event that often makes its appearance only well into adulthood.

Reprogramming of CTLs into natural killer-like cells in celiac disease

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon γ–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases.

Chronic Lyme Arthritis: Clinical and Immunogenetic Differentiation from Rheumatoid Arthritis

Ten patients with Lyme arthritis have developed chronic involvement of one or both knees. Lyme arthritis was diagnosed by onset with erythema chronicum migrans (six patients); residence in Lyme, Connecticut (eight); seasonal onset in summer and early fall (nine); early periods of short recurrent attacks (nine); absence of rheumatoid factor (nine); and absence of symmetrical polyarthritis, morning stiffness, subcutaneous nodules, or antinuclear antibodies (in all). Five patients had synovectomies; pannus formation and underlying cartilage erosion were present in all. Seven of the 10 patients had the same B-cell alloantigen, DRw2 (frequency in normal control subjects, 22% [P less than 0.005]), but did not have an increased frequency of the alloantigens associated with rheumatoid arthritis. Chronic Lyme arthritis, the result of an apparent tick-transmitted infection, resembles rheumatoid arthritis pathologically but generally differs from it in both prearticular and immunogenetic characteristics.

Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli

The molecular pathogenesis of focal/diffuse proliferative lupus glomerulonephritis was studied by cDNA microarray analysis of gene expression in glomeruli from clinical biopsies. Transcriptional phenotyping of glomeruli isolated by laser-capture microscopy revealed considerable kidney-to-kidney heterogeneity in increased transcript expression, resulting in four main gene clusters that identified the presence of B cells, several myelomonocytic lineages, fibroblast and epithelial cell proliferation, matrix alterations, and expression of type I IFN-inducible genes. Glomerulus-to-glomerulus variation within a kidney was less marked. The myeloid lineage transcripts, characteristic of those found in isolated activated macrophages and myeloid dendritic cells, were widely distributed in all biopsy samples. One major subgroup of the samples expressed fibrosis-related genes that correlated with pathological evidence of glomerulosclerosis; however, decreased expression of TGF-beta1 argued against its role in lupus renal fibrosis. Expression of type I IFN-inducible transcripts by a second subset of samples was associated with reduced expression of fibrosis-related genes and milder pathological features. This pattern of gene expression resembled that exhibited by activated NK cells. A large gene cluster with decreased expression found in all samples included ion channels and transcription factors, indicating a loss-of-function response to the glomerular injury.