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PubMed1999

Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease.

Systemic autoimmune diseases are a genetically complex, heterogeneous group of diseases in which the immune system targets a diverse, but highly specific group of intracellular autoantigens. The clustering and marked concentration of these molecules in the surface blebs of apoptotic cells, and their modification by apoptosis-specific proteolytic cleavage and/or phosphorylation at these sites, has focused attention on a unique apoptotic setting as the potential initiating stimulus for systemic autoimmunity. This apoptotic event is likely to (i) occur in a microenvironment containing high concentrations of the targeted antigens, (ii) be pro-immune in nature (e.g. viral infection), and (iii) allow suprathreshold concentrations of antigen with non-tolerized structure (either novel fragments, post-translational modifications, or complexes) to enter the class II processing pathway and initiate a primary immune response. Defective clearance or reduced anti-inflammatory consequences of apoptotic material may be important susceptibility factors in this group of diseases. Once the primary immune response to apoptotic antigens has been initiated, other apoptotic events (occurring in the course of homeostasis or damage) may stimulate the secondary immune response with less stringency, resulting in flares.

Apoptosis↗
PubMed2002

The genetic background of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and its autoimmune disease components.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder characterized by an immune-mediated destruction of endocrine tissues, chronic candidiasis, and additional ectodermal disorders. In contrast to many other autoimmune diseases, APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE). To date, 45 different mutations of the AIRE gene have been identified and are distributed throughout the entire coding region. Several of the AIRE mutations predict the transcription and translation of a truncated protein, which may be nonfunctional. In contrast to the genetic background of APECED, in all of the autoimmune conditions typically associated with APECED the conclusive role of a single genetic locus capable of providing insight into the etiology of the disease has not been identified. Here we provide an overview of the current clinical and genetic features of APECED in comparison to the genetic background of the frequently associated disease components of APECED.

Autoimmunity↗
PubMed1999

Microchimerism: implications for autoimmune disease.

Recent studies indicate cells traffic between the fetus and mother during normal human pregnancy and that fetal cells persist in maternal peripheral blood for decades after childbirth. The long-term persistence of fetal cells, when considered together with clinical similarities of chronic graft-vs-host disease and autoimmune disease and the female predilection to autoimmunity, led to the hypothesis that microchimerism is involved in some autoimmune diseases. Sources of engraftment applicable to men and to women who have never been pregnant include from a blood transfusion, a twin sibling, or mother. Initial studies lend support to the hypothesis. A role in disease pathogenesis has not been demonstrated, however, and microchimerism is also common in healthy normals. If microchimerism is involved in the pathogenesis of some autoimmune diseases further understanding potentially may lead to new therapeutic strategies.

Adult↗
PubMed1992

Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists.

The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize autoantigens and major histocompatibility complex (MHC) class II restriction molecules presented by non-immune, aberrant cells, subsequently leading to damage on healthy tissues. Psoriasis is suggested to be an autoimmune disease and in severe, uncontrollable psoriasis CsA and Mx are of value in reducing disease activity. Histamine is suggested to be involved in the pathogenesis of psoriasis and the histamine-2 receptor antagonist ranitidine has been shown to be of value to reduce severe psoriatic disease. The finding that CsA and Mx efficiently reduce histamine formation and release raises the possibility, that histamine is one of the molecules involved in pathogenesis of autoimmune diseases. T cell mediated regulation and suppression of autoreactive T cells seem to be ineffective in controlling the enhanced immune reaction in patients where the discrimination between self and non-self is changed. A consequence of this may be induction of interferon-gamma (IFN-g) production and release by cytotoxic T cells, subsequently leading to expression of MHC II molecules on non-immune tissues. As immunotherapy may be of value in some autoimmune diseases the use of histamine-2 receptor antagonists should be evaluated in patients where conventional therapy is ineffective to reduce disease activity.

Autoimmune Diseases↗
PubMed1997

[High-dose chemotherapy followed by hematopoietic stem cell transplantation as therapy for systemic rheumatic autoimmune diseases].

Remissions of autoimmune diseases can be accomplished in animals by myeloablative chemotherapy followed by allogeneic or autologous bone marrow transplantation. Remissions of autoimmune diseases have been reported in patients with concomitant malignancies for which they were treated with myeloablative chemotherapy followed by stem cell transplantation. Survival of patients with systemic rheumatic autoimmune disease is reduced. Since transplantation related mortality after autologous stem cell transplantation is less than 5%, this treatment becomes a possibility for patients with severe systemic rheumatic autoimmune disease, such as systemic sclerosis.

Adult↗
PubMed2003

Experimental autoimmune encephalomyelitis: cytokines, effector T cells, and antigen-presenting cells in a prototypical Th1-mediated autoimmune disease.

Experimental autoimmune encephalomyelitis (EAE) is widely depicted as the prototypical CD4+ Th1-mediated autoimmune disease. Microglia and perivascular macrophages are believed to act as antigen-presenting cells during the effector phase of EAE. In this article, recent data that challenge these conceptions are reviewed. Several recent studies have shown that myelin-reactive CD8+ T cells can mediate inflammatory demyelination. Furthermore, dendritic-like cells have been detected in EAE lesions and implicated in encephalitogenic T-cell activation. Although Th1 polarizing monokines, such as interleukin-12 (IL-12) and possibly IL-23, are critical for the manifestation of EAE, individual Th1 effector cytokines were found to be dispensible.

Animals↗
PubMed1982

Speculations on potential anti-receptor autoimmune diseases.

Many autoimmune disorders have a strong tendency to cluster in a single patient or type of patient. Therefore, in those cases in which anti-receptor antibodies are known to be responsible for one of the diseases in the cluster, it is logical to proceed investigatively on the presumption that the aetiology of other members of the cluster may also have an anti-receptor autoantibody basis. This logic is examined by considering examples of clustering in human diseases involving both organ-specific and non-organ-specific autoimmunities. The strong relationship between clustering among autoimmune diseases and the HLA-B8/DRw3 haplotype may provide a marker for anti-receptor autoimmune diseases.

Addison Disease↗
PubMed2006

Mechanisms of disease: atherosclerosis in autoimmune diseases.

Atherosclerosis is a pathologic process affecting blood vessels, which leads to the development of cardiovascular disease. The immune system is involved in atherogenesis and in the pathogenesis of atherosclerosis. Several autoimmune rheumatic conditions, including rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome, are characterized by enhanced atherosclerosis and consequently higher cardiovascular morbidity and mortality rates. Enhanced atherosclerosis, in these diseases, can manifest as overt cardiovascular diseases, but could be detected at an earlier stage by identification of abnormal endothelial function and arterial intima-media thickening. Both classical and nonclassical risk factors are presumed to contribute to atherosclerosis progression in rheumatic diseases. As atherosclerosis can be considered to be an immune-mediated process, several experimental strategies exist for its immunomodulation, including induction of immune tolerance. In this article, we briefly review the contribution of autoimmune elements, such as autoreactive lymphocytes and autoantibodies to atherosclerosis and discuss the nature of atherosclerosis in autoimmune rheumatic diseases.

Animals↗
PubMed1996

Prevention of lpr-graft-versus-host disease and transfer of autoimmune diseases in normal C57BL/6 mice by transplantation of bone marrow cells plus bones (stromal cells) from MRL/lpr mice.

C57BL/6 (B6) (H-2b) mice were lethally irradiated and then reconstituted with T cell-depleted MRL/Mp-lpr/lpr (MRL/lpr) (H-2k) bone marrow cells. The mice showed a short survival with splenic atrophy and fibrosis, as previously described as lpr-graft-vs-host disease (GVHD). However, when these mice received bone marrow transplantation (BMT) plus bone grafts (to recruit donor-derived stromal cells) from MRL/lpr mice, they survived for almost 1 yr without showing GVH symptoms, but showing autoimmune symptoms such as elevated serum IgG2a concentrations, autoantibody production and glomerulonephritis. When MRL/lpr bone marrow cells plus MRL/+ bones (instead of MRL/lpr bones) were transplanted into B6 mice, such improved survival was also obtained, although the MRL/+ bone grafts were less effective in prolonging survival than MRL/lpr bone grafts. H-2 typing of stromal cells in the bone marrow of the B6 mice revealed that the stromal cells had been replaced by donor(H-2k) derived stromal cells. Analyses of TCR repertoires showed that the percentage of CD4+V beta 8.1,2+ cells significantly decreased in the B6 mice that received bone marrow transplantation plus bone grafts from MRL/lpr mice. These findings suggest that stromal cells present in the bone marrow play a crucial role in the development of lpr-GVHD and autoimmune diseases.

Animals↗
PubMed1978

Self-nonself concept for cancer and diseases previously known as "autoimmune" diseases (illegitimate transferases/plasma exchange).

The illegitimate glycosphingolipid antigens of the P blood group system and of the Forssman (Fs) tissue antigen in adenocarcinoma which are foreign to the host suggest the self-nonself concept which applies also to numerous other diseases such as rheumatoid arthritis, lupus, gluomerulonephritis, and idiopathic acute hemolytic anemia. In the presence of the glycosphingolipid antigens such as ABO, P, and Fs, the normal serum of the homozygote recessive precursor contains antibodies for the missing antigen(s). The expected antibody to the Fs antigen was present in about 75% of normal men and women. In cancer sera, the incidence of anti-Fs was decreased to about 35-40%. On testing the normal population anti-Fs was present in 90% of the sera in the youngest group, and this value gradually diminished in the older groups; the incidence of the antibody in the 70-year age group was to about 60%. The rate of loss of anti-Fs with increasing years appears to parallel the gradual loss of anti-A and anti-B isoagglutinin titers. This phenomenon may be associated with the gradual diminution of protein synthesis with aging or the continuous accumulation of soluble immune complexes in the serum, or both. It is suggested that the self-nonself concept is also the basis for the pathogenesis of rhematoid arthritis, lupus erythematosus, idiopathic acute hemolytic anemia, and numerous other conditions classified as "autoimmune" diseases. Some of these diseases are induced by viruses or drugs or both. When a virus or drug attaches itself to the membrane of a tissue cell, the self is converted to nonself which, in rheumatoid arthiritis, alters its self Ig to nonself Ig.

ABO Blood-Group System↗
PubMed2001

A gene therapy approach for treating T-cell-mediated autoimmune diseases.

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS) in humans. In mice, EAE is mediated by Th1 type CD4(+) T cells specific for various myelin proteins which migrate from the periphery to the CNS. Removal or blocking of CD4(+) cells before or shortly after disease induction was shown to prevent disease onset and/or disease progression but also results in general immune suppression. Most treatment regimens for autoimmune diseases currently rely on general suppression of the T-cell compartment most commonly by steroids. In this paper, an experimental, gene therapy-based model is presented in which susceptible mice are made resistant to EAE induction by specifically down-regulating an autoreactive T-cell population. By using a retroviral gene transfer protocol, normal B cells were genetically modified to constitutively express the SJL-specific proteolipid (PLP) encephalitogenic determinant and then adoptively transferred into syngeneic hosts. To ensure appropriate presentation of the exogenous encephalitogenic peptide in association with MHC class II, the encephalitogenic sequence was fused to a lysosomal targeting sequence. Adoptive transfer of syngeneic B cells expressing the PLP encephalitogenic determinant into normal, naive, genetically susceptible mice induced PLP-specific unresponsiveness and completely protected the majority (62% and 83% using an intermediate and a high titer retroviral vector, respectively) of the animals from EAE induction. The remaining animals had a delayed disease onset and/or lower disease severity. All protected mice expressed the exogenous gene in the spleen as detected by reverse transcriptase-polymerase chain reaction.

Adoptive Transfer↗