Mansour Al-Janadi

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.

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.

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.

CD4+ Th2 cell response cytokine production in bacterial meningitis

There has been a growing body of evidence suggesting that CD4+ Th1/Th2 cell responses participate in pathologic and immunologic processes in infectious disease. Bacterial meningitis is a fatal disease of children and is associated with a spectrum of clinical syndromes. This study provides evidence of CD4+ enhanced interleukin (IL)-4 and IL-6 but decreased IL-2 and interferon-γ (IFN-γ) production, the induction of characteristic Th2 cell response cytokines in bacterial meningitis, which may play an important role in disease mechanism. Additionally, monocyte-induced enhanced IL-6, IL-8, and tumor necrosis factor-α production may be associated with distinct clinical features such as fever, seizures, and neurological sequelae. A striking finding was also the highly deficient monocyte-induced granulocyte-macrophage colony-stimulating factor production. Of particular interest, the CD8+-enhanced IFN-γ production may be required for the cytolytic activity or protective response to be maintained in this disease. Taken together, these data reveal that monocytes and CD4+ (Th2) and CD8+ subsets produce distinct cytokines in bacterial meningitis, which may exert an immunoregulatory and immunopathologic effect and thus mediate some of the clinical manifestations of the disease.

T-cell receptor α/β chain-CD3 protein complex defect in systemic lupus erythematosus: T-cell function

We describe the first case of systemic lupus erythematosus (SLE) in which peripheral blood T cells were deficient in cell surface expression of T-cell receptor alpha/beta chain (TcR alpha beta) and the CD3 protein. Because of the uncommon phenotype and because of the notion that coexpression of TcR alpha beta and CD3 is essential for antigen-specific T-cell function, in vitro functional assays were performed, showing a highly decreased proliferative response to anti-CD3 antibody and other T-cell mitogens, deficient interleukin-2 (IL-2) secretion, and impaired function to respond in autologous and allogeneic mixed lymphocyte reactions. However, the helper-inducer function of T cells was unaffected by deficient expression of the TcR alpha beta/CD3 protein complex. The relative increase of CD4+ CDw29+ helper-inducer subsets in T cells accounted for elevated secretion of two terminal B-cell stimulating factors, B-cell growth factor (BCGF) and B-cell differentiation factor (BCDF). Hence, our results suggest that the regulation of secretion of lymphokines, IL-2, and BCGF and BCDF is independently controlled in T cells, and this case illustrates the pathologic sequelae of a unique defect in T cells characteristic of SLE.

Peripheral T-cell lymphoma with unique immunologic features.

Background. The autologous mixed lymphocyte reaction (AMLR) is an important immunoregulatory phenomenon in human immune disorders. The authors have determined the phenotype and assessed the response of malignant lymph node T‐cells, from histologically and immunologically proven cases of peripheral T‐cell lymphoma, in AMLR and allogeneic mixed lymphocyte reaction (MLR) and studied the secretion of lymphokines.

Regulation of interleukin-4 production and cytokine-induced growth potential in peripheral T-cell non-Hodgkin's lymphomas

The malignant cells in tumour tissues produce cytokines/growth factors that may influence tumour growth, tumour immunogenicity and host immune response. We demonstrate that lymph node cell (LNC) purified neoplastic T cells from CD4+ peripheral T‐cell lymphoma (CD4+ PTCL) and CD8+ PTCL spontaneously, and after stimulation with anti‐CD3, secreted high amounts of interleukin‐4 (IL‐4) as compared to LNC‐purified CD4+ and CD8+ non‐malignant T cells. Furthermore, IL‐4 was observed to be the most potent cytokine that induced in vitro proliferation and growth of the malignant T cells. Moreover, malignant T‐cell‐derived IL‐4 secretion was augmented by exogeneous recombinant human interferon‐gamma (IFN‐γ) and was profoundly inhibited by IL‐2. Because IL‐4 was shown to be a locally active cytokine with a wide range of immunoregulatory properties, regulation of IL‐4 production by IFN‐γ and IL‐2 in malignant T cells may be one of the important parameters to be assessed in the design of anticancer‐specific immunotherapy. In summary, we report that malignant T cells produce IL‐4, a type 2 cytokine (Th2 cell response) that acts as a growth factor and which may play a critical role in PTCL disease mechanism.

Pattern of adult onset of polymyositis and dermatomyositis and association with malignancy.

A retrospective study of 22 adult patients with dermatomyositis (DM) or polymyositis (PM) was performed. Male to female ratio was 1:2.7. Mean age of onset was 37.3 +/- (16.3) and symptoms were present for a mean of 11.2 +/- 14.6 months before diagnosis. Primary polymyositis was diagnosed in 11 (50%), primary dermatomyositis in three (13.6%). PM/DM was associated with connective tissue disease in three (13.6%) and malignancy in five patients (22.7%). Muscle disease followed the diagnosis of malignancy by a mean of 12.2 months (one to 36 months). All were female. Diffuse erythema was observed in all three patients with DM and malignancy. Arthritis was seen more frequency in our patients (55%). Sixty-eight percent of patients showed substantial improvement of muscle disease with steroids alone or in combination with other immunosuppressive agents, 18% did not improve or their disease progressed in spite of the treatment. Three patients died (14%), two from respiratory failure and one from underlying malignancy.