Syed Raziuddin

Cytokine profile in systemic lupus erythematosus, rheumatoid arthritis, and other rheumatic diseases

We investigated serum levels of interleukin-6 (IL-6), interferon-gamma (IFN-γ), and tumor necrosis factor alpha (TNFα) from patients with systemic lupus erythematosus (SLE) and its various clinical manifestations of disease and from patients with rheumatoid arthritis (RA) and other rheumatic diseases. The serum levels of IL-6 and IFN-γ were highly elevated from patients with SLE associated with lymphadenopathy (LN) or nephrotic syndrome (NS). On the contrary, the serum levels of TNFα were elevated from most patients with SLE associated with thrombocytopenia (TP). However, serum levels of TNFα were in the normal range from patients with SLE associated with NS, LN, or central nervous system disease. Of interest, patients with SLE associated with humoral immunodeficiency disorder, hypogammaglobulinemia, had highly elevated levels of serum IL-6. The concanavalin A-stimulated mononuclear cells (MNC) of patients with SLE associated with TP secreted highly elevated levels of TNFα compared to other patient groups. We suggest that abnormal production of various cytokines in SLE is an intrinsic defect of MNC and the immune system that may be the key element for a variety of clinical manifestations of this disease.

Interleukin-10 (IL-10) secretion in systemic lupus erythematosus and rheumatoid arthritis: IL-10-dependent CD4+CD45RO+ T cell-B cell antibody synthesis

Interleukin-10 (IL-10) is a major immunoregulatory cytokine and has a multitude of immunomodulatory effects in the immune system. In this study, we have examined the secretion andin vitro function of IL-10 in B cell hyperactivity in antibody production in two common autoimmune diseases, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). IL-10 was detectable in serum of all active SLE and serum and synovial fluid samples of all RA patients but in none of the normal controls. B cells and CD4+CD45RO+ “memory” T cells secreted highly enhanced levels of IL-10 in SLE and RA versus normals. Increased IgM and IgG production by B cells-CD4+CD45RO+ T cells in SLE and RA was IL-10 dependent, since neutralization of IL-10 cytokine by anti-IL-10 antibody drastically reduced Ig synthesis in these coculture experiments. B cell hyperactivity in autoantibody production in SLE and RA may be a function of IL-10-dependent CD4+CD45RO+ Th2 cell activation. Therefore, IL-10 may play an important role in highly disturbed immune system and B cell-T cell function in these immune disorders.

Cytokine profile of viral and autoimmune chronic active hepatitis

BACKGROUND Patients with hepatitis have multiple immunologic abnormalities, which may be related to cytokine production. METHODS We examined the in vitro production of interleukins (IL-2, IL-4, IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in purified peripheral blood mononuclear cells (PBMCs) of patients with hepatitis B virus positive (HBV), acute viral hepatitis (A-HBV), HBV + chronic active hepatitis (HBV-CAH), and autoimmune-type chronic active hepatitis (AI-ACH). RESULTS IFN-gamma and TNF-alpha production were characteristically higher in patients with A-HBV than in healthy control subjects (p < 0.001). However, patients with AI-CAH produced highly elevated levels of IL-4 and IL-6 compared with patients with A-HBV and HBV-CAH and healthy control subjects. The cytokine profile (PBMC-induced IL-2, IL-4, IL-6, IFN-gamma, and TNF-alpha production) is different in A-HBV, HBV-CAH, and AI-CAH disease. The increased cytokine secretion (IFN-gamma and TNF-alpha in A-HBV and IL-4 and IL-6 in AI-CAH) could reflect altered relative frequencies of different cell phenotypes in these diseases. CONCLUSIONS Specific cytokine production may be important in the pathophysiology associated with diverse inflammatory states in patients with hepatitis.

Increased circulating HLA-DR+ CD4+ T cells in systemic lupus erythematosus: alterations associated with prednisolone therapy.

Patients with active systemic lupus erythematosus (SLE) in the circulation have a selective increase of a subset of the CD4+ helper/inducer T cells bearing HLA‐DR+, major histocompatibility complex class II antigens. We studied prednisolone‐induced alterations of HLA‐DR+, CD4+, and CD8+ T‐cell subsets in three patients with active SLE. Prednisolone therapy was accompanied by a drastic reduction in circulating HLA‐DR+, CD4+ T‐cell subsets, serum anti‐DNAtitre, normalization of the serum immunoglobulin profile, and CD4+ T‐cell responses to phytohaemagglutinin and concanavalin A. These changes in immune functions were associated with eventual improvement in the clinical condition of active SLE. A low precentage of HLA‐DR+, CD8+ T‐cell subsets was present in the circulation, which was not changed by prednisolone therapy. These results suggest that HLA‐DR+, CD4+ T‐cell subsets play a major role in the pathogenesis of active SLE, and that prednisolone‐induced immunosuppression in this disease is mediated by changes in the HLA‐DR+, CD4+ T‐cell subsets in circulating blood.

γδ T lymphocytes and proinflammatory cytokines in bacterial meningitis

BACKGROUND Patients with bacterial meningitis have a T-cell defect and impaired cytokine production. METHODS The phenotype and percentage of circulating alpha beta and gamma delta T-cell receptor-bearing lymphocytes were determined from patients with bacterial meningitis (Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis), patients with bacterial infection but without meningitis, and healthy control subjects by a monoclonal antibody staining method. The in vitro production of cytokines, interleukins (IL-2, IL-6), interferon-gamma and tumor necrosis factor-alpha was measured by the bioassay or ELISAs. RESULTS The percentage of circulating gamma delta T cells with a CD3+CD4+CD8- phenotype was significantly (p < 0.001) increased in all patients with bacterial meningitis compared with patients with bacterial infection and healthy control subjects. The CD3+ gamma delta T cells from patients with meningitis produced highly elevated levels of two proinflammatory cytokines, tumor necrosis factor-alpha and IL-6. However, interferon-gamma production was enhanced by CD3+ alpha beta T cells. CONCLUSION The increased percentage of circulating T-cell receptor gamma delta T cells and their in vitro production of tumor necrosis factor-alpha and IL-6 cytokines may play an important role in the pathogenesis and inflammatory response in bacterial meningitis.

OKT4+ T cell abnormality in patients with active systemic lupus erythematosus: HLA-DR antigen expressions

The objective of this study was to define immunologic T cell abnormality characteristic of active systemic lupus erythematosus (SLE). Eight of nine patients who had severe clinical and laboratory manifestations of active SLE had a characteristically marked increase in OKT4+ and a decrease in OKT8+ T cells. Using OKIa1 and OKDR monoclonal antibody, we found that, in circulating blood of all patients with active SLE, an increased percentage of Ia+ and DR+ T cells is present compared to inactive SLE. Five of these active SLE patients had Tac+ antigens, an interleukin 2 receptor on OKT4+ and OKT8+ T cell subsets in resting blood. The present study demonstrates that Ia+ and DR+ antigens are selectively expressed on the majority of OKT4+ T cell subsets of all patients with active SLE, whereas Ia+ and DR+ antigens are expressed almost equally on both OKT4+ and OKT8+ T cell subsets in inactive SLE. The elevated percentage of Ia+, DR+, OKT4+ T cells in active SLE was accompanied by a highly depressed proliferative response to T cell mitogens, phytohemagglutinin and concanavalin A. However, OKT8+ T cell subsets in active SLE possessed a normal proliferative response to these T cell mitogens. We conclude that this abnormality of activated OKT4+ T cells bearing HLA-DR antigens may play a role in the development of active SLE.

Circulating levels of cytokines and soluble cytokine receptors in various T‐cell malignancies

Background. Cytokines, interleukin (IL)‐4, IL‐6, interferon‐gamma (IFN‐γ), tumor necrosis factor‐alpha (TNF‐α), soluble CD23 (sCD23), and soluble IL‐2 receptors (sIL‐2R) are mediators of inflammation and immune response. Alterations in immune status of patients with various cancers may result in release of cytokines in circulation. The authors measured the circulating levels of IL‐4, IL‐6, IFN‐γ TNF‐α, sCD23, and sIL‐2R from patients with T‐cell chronic lymphocytic leukemia (T‐CLL), T‐cell acute lymphoblastic leukemia (T‐ALL) and peripheral T‐cell lymphoma (PTCL) to determine their importance in these T‐cell disorders.

Tumor Necrosis Factor Alpha Production in Schistosomiasis with Carcinoma of Urinary Bladder

Schistosomiasis parasitic infection (Schistosoma haematobium) is associated in some patients with bladder cancer. The production of cytokines such as tumor necrosis factor alpha (TNFα) is a key event of inflammation in human infectious disease and malignancy. TNFα has not been previously investigated from schistosomiasis infection and bladder malignancy. In this report we demonstrate that serum levels of TNFα are highly elevated in patients with schistosomiasis of urinary bladder (SB), schistosomiasis with carcinoma of urinary bladder (SCB), and carcinoma of urinary bladder without schistosomiasis (CB). Purified monocytes from bladder malignancy (SCB and CB) cultured without exogeneous stimuli release TNFα in the culture supernatants. However, lipopolysaccharides and concanavalin A stimulation of monocytes from these patients produced highly elevated levels of TNFα compared with normal controls. The findings that monocytes are the potent producers of TNFα in this malignancy may be a key observation implicating these cells in the pathophysiology of this disease. Furthermore, it was shown that serum TNFα levels correlated with the clinical staging of disease in both SCB and CB, with higher levels in T3 and T4 advanced-stage patients and low levels in T1 and T2 early-stage patients. These results suggest that monocyte abnormality and serum TNFα levels might be one of the factors contributing to the progression of disease.

Transient T-cell abnormality in a selective IgM-immunodeficient patient with Brucella infection

We describe here one 9-year-old female patient with an unusual form of selective IgM and CD4+ (OKT4+) helper/inducer T-cell immunodeficiency associated with Brucella infection. During the acute phase of Brucella infection, the percentage of infection. During the acute phase of Brucella infection, the percentage of peripheral blood lymphocytes (PBL) displaying OKT3+, OKT11+, and OKT4A+ phenotypes was decreased, and that of the OKT8+ cell was increased. These phenotypic T-cell abnormalities disappeared after antibiotic therapy in a 5-week period. However, the marked deficiency of CD4+ T cells and the IgM deficiency present during the acute phase of illness remained after recovery from illness. In vitro immunoglobulin production experiments during the acute phase of illness demonstrated that the patients T cells lacked the capacity to provide helper/inducer function for normal B-cell differentiation to secrete IgM. The patients T cells were also shown to possess IgM-specific suppressor cell activity on normal B- and T-cell differentiations. Thus impaired T-cell function was shown to be responsible for IgM-deficient antibody production. Defective interleukin 2 receptor expression and production by the patients PBL in response to mitogenic stimulation also were present, indicating a severe defect in the patients T-cell function.

A monoclonal antibody and functional study of malignant T cells of a patient with suppressor-T-cell lymphoma

We describe the immunologic characteristics of malignant T cells of a T-cell lymphoma patient. The neoplastic cells in lymph node expressed OKT3+, OKT11-, E-rosetting-, OKT4-, OKT8+, OKIa1+, OKDR+ suppressor-T-cell phenotype. Functionally, these malignant T cells did not respond to phytohemagglutinin, but produced a good response to concanavalin A. A defect in expression of interleukin 2 receptors was evident in phytohemagglutinin-activated T cells. In vitro immunoglobulin production experiments demonstrated that patients malignant T cells possess helper function on normal B cells to produce IgM, and suppressor function to produce IgG.