Defective Immune Regulation Research Articles

The Use of Hematopoietic Growth Factors in HIV Infection and AIDS-Related Malignancies

Human immunodeficiency virus (HIV) infection is associated with multiple defects in immune regulation and hematopoiesis. These defects include decreased proliferation of hematopoietic progenitor cells and increased destruction of mature cells. There are also disturbances of regulatory cytokines. As a result, hematopoietic cytopenias are common and the tolerance of myelosuppressive therapy is poor. One successful approach to the management of these clinical problems is the use of hematopoietic growth factors. To date, three agents have been studied in patients with HIV infection. In a Phase I trial, granulocyte macrophage-colony stimulating factor (GM-CSF) corrected leukopenia and pre-existing neutrophil defects in patients with HIV infection. In uncontrolled trials, GM-CSF also appears to reduce toxicity from zidovudine, ganciclovir, alpha-interferon, and antineoplastic therapy. In a placebo-controlled trial, erythropoietin (EPO) decreased transfusion requirements and corrected anemia in the majority of patients receiving zidovudine. In a Phase I/II trial, granulocyte colony-stimulating factor (G-CSF) also corrected leukopenia and neutrophil defects in patients with AIDS without altering HIV expression. Combined G-CSF and EPO treatment corrected both anemia and leukopenia and reduced zidovudine toxicity. New combinations of hematopoietic stimulants are being used to decrease the toxicity from cytotoxic chemotherapy in the treatment of AIDS-related malignancies. Future treatments with other recombinant cytokines may result in both reduction in myelosuppression from drug therapy and, possibly, reconstitution of the immune and hematopoietic systems of HIV-infected patients.

Primary biliary cirrhosis: Paradigm or paradox for autoimmunity

Primary biliary cirrhosis has been classified as a model autoimmune disease based on striking defects in immune regulation and the presence of autoantibodies to mitochondria. Until recently the significance and definition of mitochondrial autoreactivity was unknown. Since 1987, there has been a vast improvement in the understanding and definition of the biochemical and molecular target autoantigens. The cloning of complementary DNAs for mitochondrial antigens has led to the identification of three enzymes of the 2-oxo-acid dehydrogenase family as the targets of the autoantibodies to mitochondria in patients with primary biliary cirrhosis. The major reactive autoantigen is the E2 subunit of pyruvate dehydrogenase. Immunodominant sites on pyruvate dehydrogenase E2 (autoepitopes) have been mapped and have been shown to be the site of attachment of the functionally important lipoic acid prosthetic group. The autoepitope for the other enzymes probably occupies an equivalent site on the enzyme. The availability and definition of these mitochondrial autoepitopes have allowed specific questions to be addressed relating to the processing and targeting of these autoantigens as well as further studies on mechanisms of immunopathology. Similarly, the availability of well-defined autoantigens could contribute to the development of valid animal models in addition to the already described reproduction of the biliary ductular lesions by transfer of peripheral blood lymphocytes from patients with primary biliary cirrhosis into severe combined immunodeficient mice. Such models will facilitate specific study of the role of major histocompatibility complex expression and the characterization of T-cell reactivity. Thus, primary biliary cirrhosis is a key example of significant progress in autoimmunity being made by use of recombinant DNA technology.

Multiple myeloma--a case-control study.

A total of 399 patients with multiple myeloma and an equal number of match controls were interviewed about factors possibly related to the causes of their disease. Factors studied included occupation, chemical exposure, radiation exposure, prior diseases, immunizations, chronic infections and markers for defects in immune regulation. A strong risk associated with agriculture/food processing was observed (RR = 1.8, P = 0.002). The risk could not be restricted to those exposed to animals or meat products, or those exposed to pesticides. Significant excesses were also noted for reported exposures to chemicals and gases/fumes, but no specific agent or group of agents could be identified. Cases had fewer tonsillectomies above the age of 10 (P = 0.01). A large excess of shingles (herpes zoster) was observed in cases (P less than 0.001), but most of the excess cases occurred within 10 years of diagnosis, suggesting this was a preclinical manifestation of disease rather than a cause of it.

Patterns of Autoimmunity to Nucleoproteins in Patients with Systemic Lupus Erythematosus

The ANAs described above can be accounted for on the basis of an immune response to just three nucleoprotein structures--the nucleosome, the U1 snRNP, and the Ro particle. When these nucleoproteins are looked at in turn, the following picture emerges. The nucleosome is identified by both anti-histone and anti-DNA antibodies. Anti-histone H1 and anti-histone H2B antibodies predominate and tend to occur together. They, as well as the anti-DNA antibodies with which they appear to be linked, recognize external features of the intact nucleosome. The U1 snRNP is recognized by both anti-U1 RNP and anti-Sm antibodies. Most so-called anti-U1 RNP antisera actually contain several linked sets of different antibodies that are directed against various polypeptides (68K, A, and C) found on the U1 snRNP. Anti-Sm antibodies are linked to the occurrence of anti-U1 RNP antibodies. The Ro particle is recognized by both anti-La and anti-Ro antibodies, and almost all sera that contain anti-La antibodies also contain anti-Ro antibodies. Thus, it appears that these three nucleoprotein particles become direct focal points for autoimmune responses in SLE. It is difficult to explain such focused responses on the basis of a general defect in immune regulation or spontaneous B-lymphocyte hyperactivity. Rather it appears that these nucleoproteins themselves are directly involved in determining which B-lymphocyte clones become activated. Thus, the simplest rationalization for the patterns with which these autoantibodies occur is to invoke the possibility that the particles themselves are directly triggering autoimmune responses.

DIFFERING IMMUNE MECHANISMS TRIGGERING AUTOIMMUNITY IN PRIMARY SCLEROSING CEOLANGITIS (PSC) AND AUTOIMMUNE CHRONIC ACTIVE HEPATITIS (aCAH) OF CHILDHOOD

PSC histological features may resemble those of aCAH and increased autoantibody and IgG levels are found in both conditions. PSC, however, is less responsive to immunesuppressants. To investigate whether this derives from differences in regulatory and/or effector immune mechanisms we have studied 7 children with PSC, 14 with aCAH and 26 healthy children as controls. Lymphocyte cytotoxicity values to autologous hepatocytes were similarly elevated in 5 children with PSC (mean±SD, 50±9%) and in 7 with aCAH (53±16%) studied. In contrast, T suppressor number and Con-A induced function were normal in patients with PSC (23.5±3.1% and 50.8±5.3%), but significantly decreased in children with aCAH (15.8±4.7% and 7.6±6.5%), when compared to controls (24.2±5.4%, p<0.02 and 51.7±4.0, p<0.01 Rank Test). In 7 PSC patients percentages of activated T cells expressing HLA-DR (4.4±1.2%) or IL2r (0.2±0.3%) were similar to controls (2.92±0.3% and 0.14±0.2%) while significantly increased numbers of both were found in 14 aCAH patients (6.3±2.7, p<0.05 and 18.0±3.2 p<0.001). Our data suggest that liver damaging effector mechanisms are similar in PSC and aCAH but factors triggering autoimmunity differ. While in aCAH autoimmunity probably derives from defective T-dependent immune regulation, in PSC it could result from E lymphocyte polyclonal activation bypassing T cells.

1246 IDDM AND CONGENITAL HYPOGAMMAGLCBULIHEMIA (CHGG)

Viral and immunologic factors are believed to contribute to the development of IDDM. It is not clear if subclinical pancreatitis without islet-cell antibodies (ICA) will manifest IDDM. A 19 year old white male receiving γglobulin since infancy for CHGG developed IDDM (EG, 690 mg/dl; serum insulin <3.0 uu/ml; HbAl, 15.6%). Clinical course included recurrent infections since infancy, recurrent diarrhea and chronic lung disease. He had normal sweat Na. Fecal fat, 8.9 gm/24h (HL: <7.0). Low urinary PABA (48%), after bentiromide ingestion and improvement of diarrhea with pancreatic enzyme therapy were suggestive of pancreatic exocrine deficiency. Serum IgG, 159 mg%; IgM, 12 mg%; undetectable IgA and IgE; poor antibody responses to influenza and pneumococcal vaccine; absent B cells, but normal lymphocytes, 1095 (15%); T cells, 887 (81%), and suppressor cells, 504 (46%); deficient helper cells, 285 (26%) with reversed H:S ratio, 0.56. Hormal lymphocyte PHA stimulation and negative delayed hypersensitivity skin tests. Antibody titers were low to CMV and EBV and absent to Coxsackie B 1 to B 6. ICA and immune responses to insulin were negative. His non-diabetic brother with common variable HGG had similar immune status except for 3% B cells; normal suppressor cells, 256 (27%); helper cells, SUS (42%) and H:S ratio,, 1.36. Defective immune regulation in this patient may have fascilitated the development of subclinical pancreatitis with resulting exocrine deficiency and IDDM without ICA. To our knowledge this is the first report of association of IDDM and CHGG.

Depression of lymphocyte responses to mitogens in mangabeys with disseminated experimental leprosy

Mononuclear cells from mangabey monkeys with disseminated experimental leprosy had increasingly severe depression of blastogenic responses to phytohemagglutinin, concanavalin A, and pokeweed mitogen as the disease progressed. Blastogenic responses were not depressed in cells from mangabeys with more localized disease. Blastogenic responses of cells from normal mangabeys appeared to vary with a circannual rhythm. The demonstration of significant negative correlations between the blastogenic responses to mitogens and the percentages of OKT8 + cells suggested that the mangabey OKT8 + subset may contain cells with suppressor function. The depressed responses to mitogens by cells from monkeys with disseminated experimental leprosy were associated with relatively high percentages of OKT8 + cells. Polyclonal immunoglobulin plaque-forming cell responses to pokeweed mitogen were depressed in cells from experimentally infected mangabeys. The results indicated that defects in immune regulation may occur in experimental leprosy in mangabeys, similar in some respects to the defects that have been reported in human leprosy.

Secretory Component and Serum Immunoglobulin A Deficiencies with Intestinal Autoantibody Formation and Autoimmune Disease

SummaryA teenage boy with both secretory component deficiency and selective serum immunoglobulin A deficiency also developed pernicious anemia, insulin‐dependent diabetes mellitus, pancreatic insufficiency, lymphopenia, intestinal candidiasis, and anti‐intestinal antibody. The patient's father had pernicious anemia and diabetes mellitus while the paternal grandfather also had pernicious anemia. Because the patient had inherited the paternal grandmother's human leukocyte antigen complex, there was no direct association between pernicious anemia and the genetic markers. The presence of multiple immunologic abnormalities in a single patient supports the concept of an underlying defect in immune regulation as a central factor in the pathogenesis of these disorders.

Secretory Component and Serum Immunoglobulin A Deficiencies with Intestinal Autoantibody Formation and Autoimmune Disease

A teenage boy with both secretory component deficiency and selective serum immunoglobulin A deficiency also developed pernicious anemia, insulin-dependent diabetes mellitus, pancreatic insufficiency, lymphopenia, intestinal candidiasis, and anti-intestinal antibody. The patient's father had pernicious anemia and diabetes mellitus while the paternal grandfather also had pernicious anemia. Because the patient had inherited the paternal grandmother's human leukocyte antigen complex, there was no direct association between pernicious anemia and the genetic markers. The presence of multiple immunologic abnormalities in a single patient supports the concept of an underlying defect in immune regulation as a central factor in the pathogenesis of these disorders.

Atopic dermatitis

Atopic dermatitis is a chronically relapsing inflammatory skin disease with altered immune and pharmacologic responses. Elevated serum IgE probably reflects defective immune regulation. Various other cellular immune defects rise and fall exacerbations and remissions of skin inflammation. Increased responsiveness to cholinergic and alpha adrenergic agents may relate to abnormalities of cyclic nucleotide regulation. Recent observations of abnormal cyclic adenosine monophosphate (cAMP)-phosphodiesterase activity in atopic dermatitis may provide new insights into the pathogenesis and treatment of the disease.

Covert suppressor T cells in Crohn's disease

To determine whether patients with Crohn's disease have a defect in immune regulation, suppressor T cell activity was assessed in 16 patients with mild or inactive Crohn's disease and was compared with that of an equal number of randomly selected normal controls. Pokeweed mitogen-stimulated cultures of peripheral blood lymphocytes from patients synthesized as much IgM as those from normal controls. In addition, cocultures of patient and normal peripheral blood lymphocytes did not result in either suppression or enhancement of immunoglobulin M synthesis. In contrast to these results with cultures of peripheral blood lymphocytes, cultures containing optimal ratios of purified B cells and T cells from patients synthesized significantly less immunoglobulin M (p < 0.005) than those from normals; in fact, the latter cultures from 6 patients synthesized no detectable immunoglobulin M. Detailed studies of cells from these patients indicated that a suppressor T cell was revealed in vitro during the cell-purification procedure. Finally, in those patients in whom it could be measured, radiation-sensitive suppressor T cell activity was found to be normal. We conclude that there is no deficiency of suppressor T cells regulating antibody synthesis in patients with Crohn's disease; on the contrary, at least one-half of these patients have suppressor T cells that markedly inhibit the synthesis of immunoglobulin M, but which are revealed only after purification of the T cells.

Defective suppressor cell activity in cancer patients: a defect in immune regulation.

Although suppressor cells appear to be involved in the normal regulatory mechanism of the lymphoid system, they are also considered to have a role in the immunosuppression of certain malignancies. Suppressor activity of lymphocytes can be reproducibly measured by use of the mixed lymphocyte culture-mitogen interaction (MLC-M) in which the stimulating cell either is in the basal state or has been induced by Concanavalin A. This yields a quantitative measure of resting suppressor cell activity as well as the maximum generation of suppressor activity as induced by Con A. This test was performed, using autologous and allogenic cell combinations in a group of 13 cancer patients and 18 normal controls. Normal lymphocytes activated by Con A in 48-hour lymphocyte cultures significantly decreased the mitogenic response of lymphocytes from healthy, male donors to phytohemagglutinin (PHA), Con A, and Pokeweed mitogen (PWM) in both autologous and homologous systems. In contrast, Con A activated lymphocytes from cancer patients demonstrated diminished suppressor activity compared with controls in autologous (P less than 0.01), and allogenic (P less than 0.005) systems. There was a correlation between the degree of immunosuppression and suppressor cell activation: i.e., the patients most depressed generally had the lowest suppressor cell activation. Untreated lymphocytes from cancer patients also exerted suppressive effects on normal lymphocyte responses, suggesting an increased resting level of suppressor cells. These data suggest that in addition to having depressed cellular immune responses, cancer patients frequently have reduced capability to generate suppressor cell activity, which implies a generalized defect in this aspect of immune regulation.

Abnormal regulation of immunoglobulin synthesis in vitro in primary biliary cirrhosis

To determine whether there is a defect in immune regulation in patients with primary biliary cirrhosis (PBC), T-cell mediated help and suppression of pokeweed mitogen-induced immunoglobulin (IgM and IgG) synthesis were studied in vitro. Cultures containing unirradiated T cells and B cells from normal individuals showed augmentation of immunoglobulin (Ig) synthesis at low T:B-cell ratios (helper T-cell effect) and inhibition of Ig synthesis at high T:B-cell ratios (suppressor T-cell effect). Cultures containing irradiated T cells from normal individuals showed augmentation of Ig synthesis at all T:B-cell ratios studied, indicating marked reduction of suppressor T-cell function by irradiation. In contrast, cultures containing unirradiated T cells and autologous B cells from patients with PBC showed augmentation of Ig synthesis at high T:B cell ratios. Immunoglobulin synthesis by cultures containing irradiated T cells and autologous B cells from patients with PBC was similar to that by corresponding cultures of cells from normal subjects. Allogeneic mixtures of cells from normal individuals and patients with PBC showed that while B cells from patients with PBC synthesize normal amounts of Ig in the presence of normal T cells, T cells from patients with PBC caused marked enhancement of Ig synthesis by normal B cells. Patients with other liver diseases characterized by chronic cholestasis, cirrhosis, or hepatocellular necrosis did not exhibit an analogous abnormality of Ig synthesis in vitro to that found in PBC. Primary biliary cirrhosis is associated with a defect of immune regulation characterized by abnormally high Ig synthesis by cultures of autologous T and B cells at high T:B cell ratios, which may be due to a deficiency of suppressor T-cell function.

Altered immunity in male patients with alcoholic liver disease: evidence for defective immune regulation.

We sought evidence for altered immunity in patients with alcoholic liver disease, and we correlated the observed immunologic abnormalities with the extent of histologically proven liver disease. Total circulating lymphocytes and the absolute number of T lymphocytes were decreased in alcoholics (p less than 0.01) compared to controls. Immunoglobulins G and A were elevated significantly (p less than 0.05) in alcoholic patients with hepatic fibrosis or cirrhosis compared to controls and alcoholics without liver histopathology. In alcoholics with fibrosis or cirrhosis at time of admission, IgE levels were also elevated (p less than 0.01) but decreased 50% during hospitalization. Forty-eight percent of the patients with alcoholic liver disease had antibodies to small bowel epithelium, and 33% had antibodies to fibroblast cytoplasm. In addition, we found that alcoholics immunized with polyvalent pneumococcal polysaccharide responded with significantly elevated (p less than 0.025) antibody titers compared to hospitalized controls. In aggregate, these findings in patients with alcoholic liver disease are consistent with a defect in immune regulation.

Lymphocytotoxic antibodies in systemic lupus erythematosus patients and their relatives: reactivity with the HLA antigenic molecular complex.

Lymphocytotoxic activity of sera from systemic lupus erythematosus (SLE) patients and their families was inhibited by 50% or more by preincubation of target cells with Fab2 fragments of xenoantisera against beta 2 microglobulin or the heavy chain of the HLA-A,B,C antigenic molecular complex. An antiHLA-DR xenoantiserum had less blocking effect on peripheral blood mononuclear cells but was effective at blocking reactivity of these sera against cultured B lymphoid cell lines. The repertoire of specificities in family members' sera differed from each other and their respective proband with respect to their reactions with cultured lymphoid cell lines. These data indicate that lymphocytotoxic antibodies (LCA) found in most patients with SLE and some of their relatives include a subpopulation with specificity for determinants present on major histocompatibility gene products. They also suggest that LCA in relatives represent a defect in immune regulation which allows expression of existing autoimmune potentials rather than immunization with a single "lupus" antigen.