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Self-reactive B cells arise during development and can increase pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that self-tolerance is enforced through temporally distinct mitochondrial outer membrane permeabilization (MOMP) checkpoints. Using conditional Bcl-2 expression to inhibit MOMP either from B cell development or activation, we find that early inhibition permits survival of autoreactive B cells after peripheral egress, expanding the pool available for activation and AID-dependent diversification. This results in broadened class-switched IgG autoreactivity, complement activation, kidney pathology, and drives lethal autoimmune disease. In contrast, post-activation MOMP inhibition promotes autoreactive cell accumulation and autoantibody production but causes limited tissue damage and normal survival. Together, these findings support a Distributed Clonal Deletion Model in which temporally distinct checkpoints cooperate to constrain autoimmune disease progression.
Self-reactive B cells are generated during normal development and can acquire increased pathogenicity through activation-induced cytidine deaminase (AID)-mediated diversification following activation. Clonal deletion is thought to eliminate these cells, yet how deletion is distributed across developmental and activation stages to prevent autoimmune disease remains unclear. Here, we show that clonal deletion is enforced through temporally distinct mitochondrial apoptosis (MOMP) checkpoints that differentially regulate autoreactive B cell fate and disease progression. Using conditional Bcl-2 expression to inhibit MOMP either before or after B cell activation, we find that early inhibition permits the survival and maturation of autoreactive B cells after peripheral egress, expanding the pool of cells available for activation. These cells subsequently undergo AID-dependent diversification, producing class-switched IgG autoantibodies with expanded antigen breadth that target a wider range of self-antigens and drive lethal, female-biased autoimmune disease characterized by complement activation and kidney pathology. In contrast, inhibition of MOMP only after activation allows the accumulation of germinal center, switched memory, and plasma cells and promotes autoantibody production, but results in more restricted IgG autoreactivity, limited complement activation and limited tissue damage, and normal survival. Notably, early MOMP inhibition does not expand immature bone marrow B cells, indicating that a major clonal deletion checkpoint operates in the periphery rather than during initial B cell generation. Together, these findings support a Distributed Clonal Deletion Model in which early checkpoints restrict the entry of autoreactive B cells into diversification pathways, while later checkpoints limit the persistence of diversified autoreactive clones, thereby constraining autoimmune disease progression.
OBJECTIVE: The causal relationship between Autoimmune Diseases (ADs) and Hearing Loss (HL) remains unclear. This study investigates whether genetic predispositions associated with ADs contribute to HL risk. METHODS: Mendelian Randomization (MR) analysis was conducted to explore the causal effects of ADs on HL. SNPs from Genome-Wide Association Studies (GWAS) were used as instrumental variables for ADs, including Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome (SS), Ankylosing Spondylitis (AS), Multiple Sclerosis (MS), Crohn's Disease (CD), and Ulcerative Colitis (UC). Outcome data included Sensorineural Hearing Loss (SNHL), Conductive Hearing Loss (CHL), Mixed conductive and sensorineural Hearing Loss (MHL), and Sudden Idiopathic Hearing Loss (SIHL). MR analyses employed Inverse Variance Weighted (IVW) as the primary method, supplemented with MR-Egger, weighted median, and weighted mode. Heterogeneity, pleiotropy, and sensitivity were evaluated using Cochran's Q test, MR-Egger regression, MR-PRESSO, and leave-one-out analysis. RESULTS: The IVW method identified nine significant associations: MS-SIHL (OR = 1.0494, 95% CI 1.0072-1.0934), AS-CHL (OR = 1.2832, 95% CI 1.0643-1.5472), AS-MHL (OR = 1.5994, 95% CI 1.3696-1.8678), AS-SNHL (OR = 1.1903, 95% CI 1.1104-1.276), AS-SIHL (OR = 1.481, 95% CI 1.22-1.798), SLE-CHL (OR = 1.0593, 95% CI 1.0116-1.1092), UC-MHL (OR = 1.0907, 95% CI 1.0027-1.1865), CD-CHL (OR = 1.0529, 95%CI: 1.0074-1.1005), and CD-SIHL (OR = 1.0597, 95% CI 1.0177-1.1034). Among these, outliers were detected only in AS-SNHL. After outlier removal, the AS-SNHL association remained significant (OR = 1.1722, p < 0.00001), with resolved heterogeneity and pleiotropy. No heterogeneity and pleiotropy were found for the other associations. CONCLUSION: This study identified nine significant AD-HL associations, emphasizing the need for targeted screening and management of HL in individuals with AD. LEVEL OF EVIDENCE: Level 5.
In general, evidence of autoimmunity increase with age. The following explanations are proposed: Somatic mutations causing progressive changes in cell surfaces lead to progressive increase of antibodies which cross react with normal cell surfaces (auto-antibodies). The HLA antigens (and to a lesser extent other cell surface antigens) bind foreign molecules creating a hapten-carrier relationship which will direct the immune response to the surfaces of cells, which will most commonly be the blood and tissue leukocytes. However the HLA antigens on the surfaces of cells of some solid tissues may, for reasons intrinsic to the particular antigen and cell surface, bind haptenic material leading to an immune response directed in part against the tissue. This may be a short term event while the hapten is present, or it may continue in the absence of the hapten, directed at the carrier (cell surface) molecule alone. It may be perpetuated in some tissues (e.g. joint tissues) by the presence of immune complexes or other products of inflammation.
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Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and were long regarded as inert remnants of ancestral retroviral infections. Increasing evidence indicates that HERVs are active genomic elements capable of influencing transcriptional programs, modulating immune responses, and contributing to disease pathogenesis. Under physiological conditions, HERV expression is tightly controlled by epigenetic mechanisms; however, infections, chronic inflammation, aging, and diverse environmental stimuli can promote HERV reactivation. HERV-derived RNAs and proteins engage innate immune sensors and trigger antiviral-like responses through mechanisms of viral mimicry, leading to activation of type I interferon and other inflammatory pathways. HERV dysregulation has been associated with disease-relevant immune pathways. This review summarizes recent advances linking HERVs to autoimmune disease pathogenesis and discusses their potential translational relevance as biomarkers and therapeutic targets.
Two elderly patients who presented with symptoms of "systemic rheumatic or autoimmune disease" had high serum titers of fluorescent antinuclear antibody (ANA). Signs of malignancy were evident at the time of the first examination. T-cell dysfunction in the aged may permit the simultaneous development of autoimmunity and neoplasia. When rheumatic symptoms with a high titer of fluorescent ANA develop in elderly patients, an exhaustive search for malignancy should be considered.
Early in life, mice of four kinds [NZB, (NZB X NZW)F1, MRL/1, and male BXSB] with autoimmune disease spontaneously produced far more (greater than 3 S.D.) anti-hapten antibody-forming cells in spleens and greater concentrations of anti-hapten antibodies in sera than immunologically normal strains of mice (AKR, BALB/c, C57BL/6, DBA/1-J, DBA/2J, LG/J, 129, NZW, and female BXSB). This increased nonspecific antibody production by the abnormal animals' B cells correlated well with the spontaneous development of anti-single-stranded DNA antibodies, but not with serum levels of the viral envelope glycoprotein, gp70. These results suggest that the spontaneous formation of autoantibodies in mice whose immunologic disorder is manifested by a lupus-like disease may result from polyclonal activation of B cells by endogenous or exogenous B cell activators.
Studies in which levamisole has been used with success in the treatment of rheumatoid arthritis and other autoimmune diseases may provide information useful in cancer treatment with regard to optimal dosage regimens and methods for monitoring laboratory effects. Using the response of peripheral blood lymphocytes to phytohemagglutinin mitogen measured by the uptake of tritiated thymidine in 3-day culture, patients with rheumatoid arthritis were found to have a significantly deficient response compared to normal subjects. Levamisole treatment reversed this deficiency and normalized lymphocyte mitogen responses. These studies showed the benefit of a dose of 150 mg of levamisole compared to lower doses and also showed equal maintenance of immunocompetency with a dose of 150 mg/week compared to daily levamisole. In addition, compared to poor clinical responders, good clinical responders were shown to have a greater enhancement in mitogen response, both during the treatment period and when levamisole was added in vitro to lymphocyte culture prior to drug treatment. It was concluded that laboratory studies of lymphocyte mitogen response may contribute towards better management of patients receiving levamisole therapy.
By means of a report on a 39-years-old woman with cyclic eruption of dermatosis in praemenstruum, was caused by progesterone-sensitivity. The problem is discussed of this autoimmune-disease. It is supposed that this autoimmune-progesterone-mechanism may be of importance in gynecology.
Explanations for self-tolerance and its failure in autoimmune disease remain conjectural. Earlier deletional theories and the later clonal abortion theory as a basis for central B-cell (and possibly T-cell) tolerance seemed to conflict with various experimental and clinical observations, including those relating to the ability to induce autoimmune reactivity in normal adult animals. Accordingly, immunoregulatory controls have dominated discussions. However, there is recent compelling experimental evidence in favour of clonal abortion of B lymphocytes in the absence of T-cell help. It is proposed that two sets of regulatory systems operate at different stages in life to establish and maintain self-recognition: a central tolerance operates through clonal abortion during embryonic and early postnatal life and during childhood and beyond, ancillary regulatory systems deal with the self-reactive cells which emerge in a milieu in which helper influences interfere with clonal abortion.
Diseases of autoaggression can be produced if immunotolerance to endogenous tissue is lost. Such diseases become manifest in the pulmonary and pleura regions mainly within the framework of systemic diseases of the connective tissue (collagenoses) and of the vessels (angiitides). Lupus erythematodes disseminatus belongs to the first group which also includes rheumatoid arthritis, sclerodermia, and dermatomyositis, whereas panarteritis nodosa belongs to the second group, which comprises among others arteritis of the arteria pulmonalis, Wegener's granulomatosis, Goodpasture's syndrome and Ceelen's disease. Pleuropulmonary involvement is frequent in these systemic diseases; it is in fact the principal sign in Goodpasture's syndrome and in Ceelen's disease.
The transcription factor RORγt orchestrates Th17 lineage differentiation, thymic T cell development, and the pathogenesis of several autoimmune disorders. Lipid ligands are required for appropriate regulation of RORγt activity, but it is unclear to what extent lipid recognition controls RORγt function in vivo. Here, we show that the mutation of RORγt alanine-304 in the ligand-binding domain (LBD) to isoleucine (A304I) abrogates lipid-dependent Th17 differentiation and selectively ameliorates γδT17 cell-mediated psoriatic skin inflammation. In contrast, there is no improvement in experimental autoimmune encephalomyelitis in RORγtA304I mice. Consistent with this, the expression of genes characteristic of Th17 cells decreases in RORγtA304I mice, along with a compensatory increase of genes characteristic of Th1-like Th17 cells with pathogenic signatures. Thus, RORγt alanine-304 in the LBD is indispensable for generating γδT17 and conventional Th17 cells and for the suppression of the Th1-like Th17 pathogenic population, which decouples the pathogenicity of skin and CNS autoimmune diseases.
Serum pregnancy-associated alpha2-glycoprotein (alpha2-PAG) levels have been measured in patients with a variety of proven non-organ specific and organ-specific autoimmune diseases and in age and sex-matched hospital outpatient and inpatient controls. Significantly lower alpha2-PAG levels were only observed in patients with thyrotoxicosis and in patients with atrophic gastritis accompanied by megaloblastic anaemia. In the latter case a significant inverse correlation between alpha2-PAG and haemoglobin levels was noted.
Transcobalamin II (TC II) is a serum protein responsible for transporting vitamin B12 to the cells. A previous observation of a child with congenital TC II deficiency and agammaglobulinemia suggested that this protein plays an important role in the immune response. Accordingly, TC II levels ere determined in 32 patients with autoimmune disease (AID) (i.e. 26 with lupus erythematosus, 4 with dermatomyositis, and 2 with autoimmune hemolytic anemia) and in 40 patients with acquired immunodeficiency due to chemotherapy. It was found that elevated TC II levels corresponded to active phases of AID. Changes in TC II levels correlated better with the clinical course of AID than complement, antinuclear antibody or native DNA binding capacity. This suggests that TC II could be a valuable parameter in following up activity of AID.