The MMWR series of publications is published by the Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333.

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Sexually transmitted diseases treatment guidelines.

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNF alpha, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGF beta and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNF alpha and IL-1 produced. In rheumatoid joint cell cultures that spontaneously produce IL-1, TNF alpha was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNF alpha was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNF alpha at its apex. This led to the hypothesis that TNF alpha was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNF alpha therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNF alpha antibody have shown marked clinical benefit, verifying the hypothesis that TNF alpha is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNF alpha dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

Role of cytokines in rheumatoid arthritis

Rheumatoid arthritis (RA) is a widely prevalent (1-3%) chronic systemic disease thought to have an autoimmune component; both humoral and cellular mechanisms have been implicated. Primary osteoarthritis (OA) is considered to be distinct from rheumatoid arthritis, and here damage is thought to be secondary to cartilage degeneration. In rheumatoid arthritis, immune complexes are present that consist exclusively of immunoglobulin, implying that this is both the 'antibody' (rheumatoid factor [RF]) and the 'antigen' (most commonly IgG). Autoantigenic reactivity has been localized to the constant-region (C gamma 2) domains of IgG. There is no evidence for a polypeptide determinant but carbohydrate changes have been reported. We have therefore conducted a study, simultaneously in Oxford and Tokyo, to compare in detail the N-glycosylation pattern of serum IgG (Fig. 1) isolated from normal individuals and from patients with either primary osteoarthritis or rheumatoid arthritis. The results, which required an evaluation of the primary sequences of approximately 1,400 oligosaccharides from 46 IgG samples, indicate that: (1) IgG isolated from normal individuals, patients with RA and patients with OA contains different distributions of asparagine-linked bi-antennary complex-type oligosaccharide structures, (2) in neither disease is the IgG associated with novel oligosaccharide structures, but the observed differences are due to changes in the relative extent of galactosylation compared with normal individuals. This change results in a 'shift' in the population of IgG molecules towards those carrying complex oligosaccharides, one or both of whose arms terminate in N-acetylglucosamine. These two arthritides may therefore be glycosylation diseases, reflecting changes in the intracellular processing, or post-secretory degradation of N-linked oligosaccharides.

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Association of rheumatoid arthritis and primary osteoarthritis with changes in the glycosylation pattern of total serum IgG.

Murine epidermal Langerhans cells (LC) have been studied in tissue culture and compared to spleen dendritic cells (DC). LC comprised 3% of the starting cell suspensions and were distinguished from keratinocytes by cytology and reactivity with anti-Ia and anti-Mac-1 monoclonal antibodies. The LC were nonadherent, had a low buoyant density, did not proliferate, and could be enriched to 10-50% purity. LC continued to exhibit Ia and Mac-1 antigens for 4 d in culture. However, LC rapidly lost Birbeck granules, Fc receptors, F4/80 antigen, and cytochemical reactivity for nonspecific esterase and membrane ATPase. As a result, the ultrastructure and phenotype of cultured LC became remarkably similar to lymphoid DC. Stimulatory capacity for T cell proliferative responses (oxidative mitogenesis and the mixed leukocyte reaction) was monitored daily. Initially, stimulatory capacity was very weak, even though LC expressed substantial levels of Ia antigens. After 2-3 d in culture, LC had become 3-10 times more potent than spleen DC. 30 LC could induce significant responses in cultures of 3 X 10(5) responding T cells. Removal of Ia+ LC at the start of culture ablated the development of stimulatory activity, but exposure to 1,500 rad of ionizing irradiation did not. Mixing experiments showed that contaminating Ia- epidermal cells did not alter the function of Ia+ stimulators. Therefore, LC seem to be immunologically immature, but acquire many of the features of spleen DC during culture. We suggest that functioning lymphoid DC may, in general, be derived from less mature precursors located in nonlymphoid tissues.

/pdf/murine-epidermal-langerhans-cells-mature-into-potent-4ro65fi1i9.pdf

Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro.

Atherosclerosis is an inflammatory disease. Its lesions are filled with immune cells that can orchestrate and effect inflammatory responses. In fact, the first lesions of atherosclerosis consist of macrophages and T cells. Unstable plaques are particularly rich in activated immune cells, suggesting that they may initiate plaque activation. We have seen a rapid increase in the understanding of the mechanisms that govern the recruitment, differentiation, and activation of immune cells in atherosclerosis. Experimental research has identified several candidate antigens, and there are encouraging data suggesting that immune modulation as well as immunization can reduce the progression of the disease. This review provides an overview of our current understanding of the role of immune mechanisms in atherosclerosis.

Immune mechanisms in atherosclerosis.

THE major histocompatibility complex (MHC) of mouse and man controls the expression of several cell surface antigens1. The classical transplantation antigens are present on most if not all adult, nucleated cells. However, molecules controlled by the immune response region of the MHC display a much more restricted tissue distribution. The immune response-associated antigens (the Ia antigens in the mouse and HLA-D antigens in man) seem to be integral parts of the plasma membrane of B and T lymphocytes, macrophages, spermatozoa, and epidermal cells2. The physiological role of the Ia antigens is far from understood but their participation in various immunobiological events is well documented (for a review, see ref. 3). In addition to their role as triggers in the mixed leukocyte reaction4, the Ia antigens are required for collaboration between T and B lymphocytes5 and between macrophages and T cells6. Since all known functions of the Ia antigens pertain to the immune system it seemed that they should be expressed on an epidermal cell population involved in immune reactions. We therefore set out to investigate which of the three cell types of epidermis, keratinocytes, melanocytes, and Langerhans cells, expresses the Ia antigens, and from the results of fluorescent antibody staining we conclude that it is the Langerhans cells.

Epidermal Langerhans cells express Ia antigens.

Originating from observations on similarities between the rheumatoid synovial tissue and skin lesions in delayed-type hypersensitivity reactions--similarities as to massive infiltrates of "helper" T lymphocytes close to HLA-DR-expressing macrophage/dendritic cells--a notion is formed on the importance of local macrophage-dependent helper T-cell activation in the rheumatoid joint similar to that in a delayed-type skin reaction. In vitro studies on suspended synovial cells have been used to test and qualify these ideas. It is shown that (i) HLA-DR-expressing cells in normal synovial intima can, like epidermal Langerhans cells, mediate T-cell activation; (ii) the large numbers of rheumatoid synovial HLA-DR-expressing macrophage-like/dendritic cells are heterogeneous and mediate either efficient activation or suppression of T-lymphocyte proliferation, and (iii) specificity of rheumatoid T cells can be analyzed with the help of autologous synovial antigen-presenting cells; a specific anti-collagen type II response is reported in three patients.

https://www.pnas.org/content/pnas/79/11/3632.full.pdf

Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis.

UNLIKE the classical transplantation antigens, called HLA-A,B,C in man and H-2K,D in mouse, the HLA-DR (la) antigens have a restricted tissue distribution1. Primarily cells belonging to the immune system express Ia antigens whose only known biological role is to participate in cell-to-cell cooperation events involving lymphocytes and macrophages2–4. However, cells of the immune system do not only interact among themselves but they also associate physically with other types of cells like epithelial cells of the intestine and the lactating mammary gland5 and with reticuloepithelial cells of the thymus6. The possibility that all such interactions are under la antigen control is raised by indirect immunofluorescence analyses which show that la antigens are expressed on a great variety of epithelia. We report here our examination of several cryostat sections of guinea pig tissues for the presence of la antigens by indirect immunofluorescence. To obtain staining patterns that were reproducible and significantly different from the controls it proved necessary to use immunosorbent-purified heteroantibodies (see legend to Fig. 1 for description of the antibodies).

Occurrence of Ia antigens on tissues on non-lymphoid origin

An immunohistochemical double staining technique was used to study the relationships between HLA-DR-expressing, mostly macrophage-like cells, and different populations of T lymphocytes in frozen sections of synovial tissue from patients with inflammatory joint disease, particularly rheumatoid arthritis. Substantial T-lymphocyte infiltration as measured by Leu 1 antibody binding was found, especially adjacent to HLA-DR-expressing cells near the synovial cavity and around small vessels. Most of the T cells reacted with Leu 3a ('helper/inducer'-cell-specific) antibodies, whereas relatively few cells were Leu 2a ('cytotoxic/suppressor' T-cell-specific)-positive.

Relationships between HLA‐DR‐expressing Cells and T Lymphocytes of Different Subsets in Rheumatoid Synovial Tissue

The reactivity of rabbit anti-HLA-DR antigen antibodies with cells in normal and rheumatoid synovial tissue was investigated by indirect immunofluorescence on frozen sections of tissue. The antibodies reacted with a significant proportion of the synovial lining cells of both normal and rheumatoid synovial tissue, with endothelial cells, and with a number of, most probably, migratory cells. After dispersion of cells from rheumatoid synovial tissue by digestion with collagenase and DNase, adherent cells of both a macrophage-like and a dendritic appearance reacted with the anti-HLA-DR antigen antibodies. The adherent cells were also found to be potent stimulators in the allogeneic MLR. In addition, it was found that a high percentage of T lymphocytes from both peripheral blood and synovial tissue of rheumatoid patients bound anti-HLA-DR antibodies. The present data suggest a role for synovial lining cells in HLA-D-locus-dependent events of importance in the pathogenesis of rheumatoid arthritis and other joint diseases and point to the need for further investigations on T lymphocytes derived from the site of inflammation in the study of rheumatoid arthritis.

Urban Forsum

Papers

Epidermal Langerhans cells express Ia antigens.

Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis.

Occurrence of Ia antigens on tissues on non-lymphoid origin

Relationships between HLA‐DR‐expressing Cells and T Lymphocytes of Different Subsets in Rheumatoid Synovial Tissue

Appearance of Anti‐HLA‐DR‐Reactive Cells in Normal and Rheumatoid Synovial Tissue