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Peripheral blood mononuclear cells from patients with either Crohn's disease or ulcerative colitis (collectively referred to as inflammatory bowel disease) are cytotoxic in vitro for isologous or allogeneic colonic epithelial cells. Utilizing the ability of thymus-derived (T) lymphocytes to bind sheep red blood cells to their surface and the property of bone marrow-derived (B) lymphocytes to display easily detectable surface immunoglobulin determinants, the cytoxicity of these lymphocyte subpopulations was tested. The results indicate that the mononuclear cell required for the lysis of colonic epithelium was not included within the bulk of T or B lymphocytes. Indeed, enrichment for cytotoxicity correlated best with enrichment for a mononuclear cell population lacking classical T or B markers. Additionally, mononuclear cells specifically adhering to plastic petri dishes coated with heat-aggregated immunoglobulin, and thus presumably bearing a surface Fc receptor, were enriched in their cytotoxicity. Alternatively, cells not adhering to aggregated Ig-coated petri dishes were relatively depleted of cytotoxicity. The implications of these findings as they relate to possible interactions between cellular and humoral immune mechanisms as a pathogenic mechanism for the colonic inflammatory process noted in patients with inflammatory bowel disease are discussed.

The immunologic responses, both cell-mediated and humoral, to exogenous antigens reflect a crucial balance between extrinsic forces which can either augment or suppress the reactivity of T and B effector cells. It is probable that similar immunoregulatory influences play a key role in maintaining tolerance to some self-antigens. Thus, despite the presence of cells potentially capable of reacting to autologous antigens, lack of autoimmunity might reflect either an absence of amplifying or a preponderance of suppressive immunoregulatory forces. Within this framework, data obtained indicating aberrances of immunoregulation in patients with systemic lupus erythematosus are discussed, specifically as the aberrances may be causally related to the autoimmune nature of this disease.

Sufficient data exist to implicate the monocyte-macrophage as the major source of prostaglandins in monocyte-macrophage-T lymphocyte interactions. Prostaglandin (PG) E2, a major prostaglandin synthesized by human monocyte-macrophages is able to modulate a variety of T lymphocyte reactivities including blastogenesis, lymphokine secretion, and cytotoxicity. The effect of PGE2 on T lymphocyte function varies according to the primary activating stimulus, the specific response under investigation, as well as the population of T lymphocytes involved. Some immunologic abnormalities found in clinical disease may in part derive from alterations occurring in the synthesis of PGE2 by monocyte-macrophages or in the response of T lymphocytes to PGE2.

We have introduced a full-length complementary DNA of the T-cell antigen receptor beta-chain into a mutant human T-cell line that lacked a complete beta-chain messenger RNA, had a diminished level of alpha-chain transcript and did not express surface T3- or antigen receptor. Expression of the transfected beta-chain led to a normal level of alpha-chain transcript and a structurally and functionally active T3 T-cell antigen receptor complex on the cell surface.

Prostaglandins (PG) of the E series, PGE(1) and PGE(2) (PGEs), can induce elevations of intracellular cyclic AMP (cAMP) among thymus-derived (T) lymphocytes (T cells) and inhibit their reactivity. For example, 0.1 muM of PGEs induces a two- to threefold increase of intracellular cAMP among human peripheral blood T cells and a 20-30% suppression of their blastogenic response to phytohemagglutinin. However, this suppression actually represents the net reactivity of T-cell populations demonstrating quite different responses to PGEs. Fractionation of T-enriched populations on a discontinuous density gradient yields a population of high density cells whose phytohemagglutinin-induced blastogenic response is suppressed 60%; a population of intermediate density cells whose response is suppressed 20%; and a population of low density T cells whose response is not suppressed, but is enhanced 20% by both of the PGEs. The diametrically opposite responses of low and high density T cells to the PGEs is not related to any difference in their intrinsic mitogen reactivity nor is it influenced by interactions with other T cells, bone marrow-derived (B) cells, or monocytes. Moreover, the distinct blastogenic response of low and high density T cells to PGEs does not simply correlate with PGE-mediated activation of adenylate cyclase. PGE(2) induced comparable absolute and identical relative increases of intracellular cAMP among the low and high density T cells. Cholera toxin, a potent activator of adenylate cyclase, and exogenous 8-bromo cAMP mimicked the effects of the PGEs on these two T-cell populations. These data demonstrate that T cells are heterogeneous with regard to their response to the PGEs. Thus, PGEs should be considered as potential regulators rather than as universal suppressors for T-cell reactivity. Moreover, the effect of PGEs on the blastogenic response of a given T-cell population depends upon intracellular events which occur subsequent to elevations of cAMP.

The ability of monocytes/macrophages to regulate various aspects of immunologic responses may in part depend on their release of soluble substances such as prostaglandins. Using quantitative gas-liquid chromatography/mass spectrometry, prostaglandin E2 was found to be the major prostaglandin synthesized in culture by human peripheral blood monocytes. Subjecting these cells to discontinuous density gradient fractionation demonstrated significant differences in the synthesis of prostaglandins E2 and E1 among the resulting monocyte subpopulations.

Several studies have demonstrated that the expression of Ia molecules by macrophages is not constitutive but can be enhanced by soluble factors from activated T cells. This induced expression of Ia appears to be causally important in certain accessory functions such as antigen presentation. While the phenomenon of Ia induction is clear, the mechanism by which this occurs has not been determined. Therefore, experiments were designed to investigate the molecular events leading to expression of the human Ia molecule, HLA-DR. To accomplish this, the human monocytoid cell line U 937, which does not express any detectable HLA-DR molecules were used. Utilizing a cDNA probe for the alpha chain of HLA-DR and total cellular RNA, it could be demonstrated that resting U 937 lacked detectable HLA-DR transcripts. Digestion of genomic DNA from U 937 with the isoschizomers Msp I and Hpa II followed by analysis of the restriction fragments on Southern blots demonstrated the HLA-DR alpha chain genes to be methylated. Addition of 5-azacytidine, an analogue of cytidine which causes hypomethylation of DNA to U 937 caused hypomethylation of HLA-DR alpha chain genes but did not, by itself, lend to the appearance of HLA-DR molecules or transcripts. However, treatment of U 937 with 5-azacytidine followed by addition of either culture fluids from activated T cells or human recombinant gamma interferon did lead to the rapid appearance of abundant, mature HLA-DR transcripts and surface HLA-DR molecules. The results of these studies provide the first demonstration that methylation plays a role in the expression of human Ir genes and that induced expression of Ia molecules by soluble factors from T cells, including gamma interferon, is accompanied by the rapid appearance of Ir gene transcripts.

The autologous mixed lymphocyte reaction (AMLR) represents the proliferation of T cells in response to signals from autologous non-T cells. Fractionation of the non-T population into B enriched and macrophage enriched cells demonstrated that both could serve as effective stimulator cells in the AMLR. Cytolytic treatment of both populations with a macrophage specific, monoclonal antibody abrogated stimulation of the macrophage but not the B cell population. Utilizing a series of negative selection procedures - cytolysis with T cell specific monoclonal antibody, metabolic suicide with 5-bromo-2-deoxyuridine (brdU) and light - it could be demonstrated that T cells responding to autologous macrophage were distinct from those responsive to autologous B cells. Studies of the AMLR reactivity to B cells and macrophage in a small number of patients with active systemic lupus erythematosus (SLE) demonstrated that although reactivity to both populations was diminished, the response to autologous B cells was reduced more than the response to autologous macrophage. These studies suggest that the AMLR represents the sum reactivities of two responder T cells. Moreover, they suggest that a relatively selective deficiency in only one of these cells may occur in SLE.

T lymphocytes prelabeled with [14C] arachidonic acid failed to synthesize any eicosanoids even following stimulation with phytohemagglutinin, but they did release free [14C] arachidonic acid. Co-culture of unlabeled monocytes with the prelabeled T lymphocytes resulted in the synthesis of [14C] thromboxane B2, a major monocyte-derived eicosanoid. These data show that monocytes can utilize T lymphocyte-derived arachidonic acid for the synthesis of eicosanoids.

T cells capable of proliferating in response to signals from autologous cells can be demonstrated in normal peripheral blood. The stimulating cell is contained among populations enriched in B cells, "null" cells, and monocytes, but not among populations enriched in T cells. Density gradient fractionation indicated that the autologous reactive T cell may represent a subpopulation of cells responsive in allogeneic mixed lymphocyte cultures. This was confirmed by negative selection (BUDR and light) experiments which also indicated that the "autologous" stimulus can be mediated by at least some allogeneic cells. In a portion of patients with active systemic lupus erythematosus, autologous reactivity was reversibly blocked. Prior incubation of either responding T or stimulator cells at 37 degrees C restored this reactivity.

Monoclonal antibodies to the T-cell antigen receptor can mimic the effects of antigen and induce cellular activation. In this article john Imboden and his colleagues report on the use of these antibodies as probes to study the mechanism by which the antigen receptor initiates activation. They also describe the critical role of cytoplasmic free calcium in transmembrane signal transduction by the T-cell antigen receptor., (Copyright © 1985. Published by Elsevier B.V.)

Acquired immunodeficiency syndrome indicates opportunistic infection or unusual malignancy associated with a marked deficiency of cell mediated immunity in the absence of any other cause of the immune defect. This review examines epidemiology, virology, and immunology associated with this disorder. The syndrome appears to be caused by infection of at-risk individuals by a retrovirus that has tropism for a specific population of T lymphocytes.

Progressive liver injury in chronic active liver disease is usually associated with elevation of serum immunoglobulin levels. However, the role of immunoglobulins in the pathogenesis of this disease is still obscure. We report here the case of a 41-year-old man with hypogammaglobulinemia since at least 1964 in whom chronic active liver disease later developed. From 1954 he had had frequent respiratory tract infections, and these continued, along with diarrhea, despite regular gamma-globulin therapy. Studies in 1969 showed absent serum IgA and IgM and an abnormally low level of IgG. In 1974, liver enzyme abnormalities were recorded and a diagnosis of chronic active liver disease was made. A liver biopsy showed cirrhosis with active hepatitis. Lymphocyte function studies revealed that the T cells suppressed B-cell maturation and production of immunoglobulins. He was treated with azathioprine and prednisone, and this therapy has been associated with a decrease in both the elevation in liver enzymes and the frequency of infections. This case suggests that liver cell injury in chronic active liver disease is independent of the elevation of immunoglobulins and that immunosuppressive therapy may be well tolerated by patients with hypogammaglobulinemia.

Circulating antibodies to native and denatured types I and II human and bovine collagens were assayed in patients with rheumatoid arthritis (RA), patients with other rheumatic diseases, and normal individuals. A subgroup of this population was also assayed for reactivity with typing reagents which detect determinants (MT and HLA-DR) present in human immune response gene products. The mean titers of antibodies to each collagen tested were not significantly higher in RA patients when compared with patients who had other rheumatic diseases. Although both MT3 and MT4 were significantly associated with RA, there was no significant association between the anticollagen antibodies and any MT type or HLA-DR4. These studies raise a question concerning the role of collagen antibodies in the pathogenesis of RA and suggest that genes distinct from those coding for HLA-DR may play a role in the expression of the disease.

Sucrose density gradient analysis of the fresh sera of patients with hereditary ataxia telangiectasia, disseminated lupus, and Waldenström's macroglobulinemia revealed the presence of an immunoglobulin possessing IgM determinants but having a sedimentation coefficient of approximately 7 S. Bio-Gel chromatography of patients' sera confirmed the presence of two distinct populations of IgM. The low molecular weight IgM possessed incomplete isohemagglutinin activity that was resistant to treatment with reducing agents. Gel diffusion analysis revealed that the 7 S IgM showed immunological identity with both 19 S IgM and the subunits of the 19 S IgM produced by reduction. Approximately 10 to 15% of the patient's total IgM was low molecular weight. Evidence is presented that the 7 S IgM was not produced from the patient's serum 19 S IgM on in vitro incubation. A simple rapid technique is described, using double diffusion in polyacrylamide gels, which permits the determination of low molecular weight IgM in sera and other fluids. Using this technique, the sera of 52 patients with disseminated lupus were surveyed, and 17% of the patients were found to contain low molecular weight IgM. The low molecular weight IgM occurred with particular frequency in male patients with disseminated lupus and in those patients with low or absent serum IgA.Studies of the salivary immunoglobulins of patients with ataxia telangiectasia and disseminated lupus suggest an iverse relationship between the levels of IgA and IgM. In patients lacking salivary IgA, IgM was the major immunoglobulin present. No correlation was observed between salivary immunoglobulin levels and the severity of sinopulmonary infections in these patients.

An appreciable percent (3-14%) of the lymphocyte-like cells of the mouse spleen lack both the theta-isoantigen and sufficient surface immunoglobulin to be detected by conventional immunofluorescence or autoradiographic procedures. These theta(-),Ig(-) cells are increased in frequency after treatment of mice with antithymocyte serum or in mice that have been thymectomized, irradiated (850 R), and reconstituted with bone marrow cells. Moreover, in chimeric C57BL/6 mice in which the T cells are derived from (BALB/c x C57BL/6)F(1) donors, theta(-),Ig(-) cells also lack BALB/c histocompatibility antigens. These experiments indicate that theta(-),Ig(-) cells are not theta(-) T lymphocytes. Removal of complement receptor lymphocytes from spleen cell populations increases the frequency of theta(-),Ig(-) cells, indicating that such cells lack the complement receptor. Partially purified populations of theta(-),Ig(-) cells have been obtained by cytolysis by anti-theta- and anti-kappa-antibody and complement and by density gradient ultracentrifugation. These cells closely resemble lymphocytes in morphology. The only exceptional feature is the existence of prominent nucleoli. The theta(-),Ig(-) cells lack hemoglobin and endogenous peroxidases, are not actively phagocytic, and do not adhere to glass. This suggests they are not of the erythroid, myeloid, or monocytoid lines. [(3)H]Thymidine labeling studies indicate that theta(-),Ig(-) cells are members of a relatively slowly dividing cell pool. Whether theta(-),Ig(-) cells are members of the "classical" B lymphocyte line or belong to another, as yet undescribed, lineage is not yet certain.

The capacity of lymphoid cells from nonsensitized mice to lyse antibody-coated target erythrocytes in vitro does not require the presence of thymus-derived or thymus-dependent lymphocytes. Thus, spleen cells from thymus-deprived mice and spleen cell populations from which thymus-dependent lymphocytes had been removed were fully competent to mediate destruction of antibody-coated target cells. However, prior treatment of spleen cell populations with antibody to kappa chains diminished this function, suggesting a role for bone marrow-derived lymphocytes.