Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus

Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell-derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.     

Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects

OBJECTIVE: In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders. RESEARCH DESIGN AND METHODS: In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay). RESULTS: The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes-associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recentonset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive-specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05). CONCLUSIONS: We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre-type 1 diabetes.     

Update of autoantibodies in neurologic disease.

Many neurologic disorders recently have been discovered to have an autoimmune basis with autoantibodies that are responsible for neurologic symptoms and progression of the disease. Diagnosis and treatment of these disorders are facilitated by detection and monitoring of several autoantibodies. Some tumors express protein antigens shared by neurons, and an antitumor immune response leads to autoimmune antineuronal reactions exemplified by "paraneoplastic cerebellar degeneration." Other antibodies react with gangliosides present in many locations of the nervous system, leading to motor neuron damage and polyneuropathy. Phospholipid antibodies indirectly cause neurologic syndrome largely through thrombosis of cerebral vessels; other autoantibodies also have associations with specific neurologic symptoms.     

Encéphalites auto-immunes et encéphalites paranéoplasiques : ce que le réanimateur doit savoir

Autoimmune encephalitis are rare conditions that can be triggered by a cancer. Two groups of encephalitis differ depending on the type of autoantibodies that are associated with it. In the presence of onconeuronal antibodies, which are usually directed against an intracellular antigen, a cancer is frequently found and there is a diffuse neuronal loss compromising the functional prognosis. Conversely, when autoantibodies are directed against a synaptic protein, cancers are less frequent and the symptoms are related to a reversible synaptic dysfunction that is mediated by the autoantibodies.The clinical picture differs depending on the target of the associated antibody. Autoimmune encephalitis most often presents a subacute central nervous system impairment predominantly involving limbic structures and leading to behavioral or psychiatric disorders, amnesia and temporo-mesial seizures. Extra-limbic signs, especially autonomic symptoms and movement disorders, may be seen as well. Impairment of consciousness, central hypoventilation due to autonomic impairment and status epilepticus can be seen at the onset of the disease.Temporo-limbic hyperintensities on brain MRI and signs of inflammation in the lumbar puncture are suggestive, but their absence does not eliminate the diagnosis. The search for a possible underlying cancer is urgent and must be guided by the antibodies found.The management of autoimmune encephalitis must be guided by the antibodies found in patients, focusing on the search for an underlying cancer and immunosuppression.     

Cardiolipin liposomes: a novel flow reagent for detection of anticardiolipin antibodies

The association of autoantibodies with specificity for phospholipids and an increased risk for thromboembolic phenomena has received considerable recent clinical attention. These autoantibodies have been reported in patients with defined autoimmune disorders as well as in patients with no other obvious autoimmune disease symptoms other than isolated or recurrent thromboembolic disease. A significant component of this autoimmune response appears to be related to cardiolipin-directed antibodies. Most studies reported to date have used either an enzyme immunoassay or a radioimmunoassay for detection and quantitation of antiphospholipid antibodies. We have developed a novel flow cytometric assay for detection of anticardiolipin antibodies. The assay, by analogy to polystyrene microsphere assay, utilizes cardiolipin liposomes as solid-phase microspheres for antigen presentation. In comparison to enzyme-linked immunosorbent assay, the flow assay shows similar sensitivity by serum titration, has immunoglobulin class specificity, and is semiquantitative as currently designed. The flow assay is relatively easy to perform and should allow detection of other antiphospholipid specificities with tailoring of the phospholipid makeup of the liposomes.     

The clinical value of intracellular autoantigens B-cell epitopes in systemic rheumatic diseases

A hallmark of autoimmune diseases is the production of autoantibodies against intracellular autoantigens. Although their pathogenetic and their etiologic relationship are not fully understood, these autoantibodies are important tools for establishing the diagnosis, classification and prognosis of autoimmune diseases. Systemic rheumatic diseases are among the most complex disorders because their clinical presentation and constellation of findings are in part reflected by the wide spectrum of autoantibodies found in the sera of patients suffering from these disorders. These autoantibodies usually target large complexes consisting of protein antigens noncovalently associated with (ribo)-nucleic acid(s), like the spliceosome or Ro/La-RNPs. In this review, we first address the main characteristics and the clinical value of several autoantibodies, with respect to their diagnostic sensitivity and specificity. Subsequently, we provide a brief overview of the antigenic determinant types that have been identified on the corresponding autoantigens. The antibody targets of autontigens include primary, secondary, tertiary and quarternary structure epitopes, as well as cryptotopes, neoepitopes and mimotopes. We next focus on antigenic structures corresponding to B-cell epitopes with high disease specificity and sensitivity for all the major autoantigens in systemic autoimmunity including the Ro/La and U1 ribonucleoprotein complexes and the Ku70/80, ribosomal P, DNA topoisomerase I, filaggrin, Jo-1 and PM/SCl-100 autoantigens. These epitopes, defined at the peptide level, can be chemically synthesized and engineered for the development of new inexpensive and easier to perform assays and the improvement of the methods for autoantibody detection. Specific examples of newly developed assays that incorporate (i) epitopes with high disease specificity and sensitivity, (ii) modified epitopes, (iii) conformational epitopes and (iv) complementary epitopes are discussed in detail. Finally, we examine the potential of combining these synthetic epitopes for future development of multiplex diagnostic tests based on miniaturized autoantigen arrays.     

Prediction and diagnosis of type 1 diabetes using beta-cell autoantibodies

The clinical manifestation of type 1 diabetes is the endpoint of a long-lasting immune-mediated destruction process of the B-cells. Autoantibodies originating from this process can be applied in the diagnosis and clinical discrimination of autoimmune diabetes as well as in the prediction of this disease. At clinical diagnosis between 80-90% of patients with type 1 diabetes are positive for antibodies to B-cell antigens, such as ICA and antibodies to glutamic acid decarboxylase or IA2. These antibodies can also be detected in the presymptomatic period before onset of the disease, and can thus be used to predict type 1 diabetes. Using a combination of antibodies, diabetes can be predicted in 70-80% of future cases of diabetes, with a positive predictive value between 30-80%, depending on the type of antibody tested for and the population studied. Between 5 and 30% of patients initially diagnosed with type 2 diabetes will show progression to insulin dependency and turn out to have type 1 within three years of diagnosis. It is clinically relevant to identify these patients early in the course of disease, as deterioration of metabolic control results in an increased risk for macro- and micro-vascular complications. Autoantibodies to glutamic acid decarboxylase or ICA are of high diagnostic sensitivity in these cases and are better predictors for future insulin dependency than biochemical or clinical parameters. Increasing knowledge on the applicability of antibodies for diabetes prediction and diagnosis and the development of commercial assays for antibodies to glutamic acid decarboxylase and IA2 antibodies has enabled the implementation of B-cell autoantibodies in routine diagnostic settings.     

B cells in health and disease

B cells play a key role in regulating the immune system by producing antibodies, acting as antigen-presenting cells, providing support to other mononuclear cells, and contributing directly to Inflammatory pathways. Accumulating evidence points to disruption of these tightly regulated processes in the pathogenesis of autoimmune disorders. Although the exact mechanisms involved remain to be elucidated, a fundamental feature of many autoimmune disorders is a loss of B-cell tolerance and the inappropriate production of autoantibodies. Dysfunctional immune responses resulting from genetic mutations that cause intrinsic B-cell abnormalities and induction of autoimmunity in the T-cell compartment by B cells that have broken tolerance may also contribute to these disorders. These findings provide the rationale for B-cell depletion as a potential therapeutic strategy in autoimmune disorders and other disease states characterized by inappropriate immune responses. Preliminary results with the CD20-targeted monoclonal antibody rituximab indicate that rituximab can improve symptoms in a number of autoimmune and neurologic disorders (including rheumatoid arthritis, systemic lupus erythematosus, and paraneoplastic neurologic syndromes). Additional studies are warranted to further characterize the role of B cells in autoimmune diseases and the therapeutic utility of B-cell depletion.     

Predicting type I diabetes

Currently, there are three markers that are being studied with the potential to give a high positive predictive value for the development of type I diabetes (insulin-dependent diabetes caused by autoimmune beta-cell destruction) and that can be utilized to predict the disease in susceptible relatives: 1) high-titer cytoplasmic islet cell antibodies, 2) insulin autoantibodies detected with fluid-phase radiobinding assays, and 3) first-phase insulin release after intravenous glucose less than 1st percentile. With the combination of these assays, it seems to be possible to identify first-degree relatives with a high probability of developing type I diabetes within a limited time span (i.e., less than 10 yr). The ability to predict type I diabetes with selected assays will allow trials for prevention of diabetes and trials to assess whether prediction will decrease morbidity and mortality at onset of diabetes.     

Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon

Alpha interferons have become effective palliative treatments for patients with neuroendocrine tumours such as carcinoids and endocrine pancreatic tumours. However, several reports indicate an increased incidence of both autoantibodies and autoimmune diseases in patients treated with interferon-alpha (IFN-alpha). We studied the development of antibodies against double-stranded DNA (dsDNA) and clinical signs of autoimmune disease in 214 patients with malignant carcinoids or endocrine pancreatic tumours consecutively admitted for treatment with IFN-alpha. Seventeen patients (8%) developed antibodies against dsDNA, predominantly females (12 females and 5 males). One patient had clinical and laboratory signs of polymyositis. Among the other 16 patients, three developed hypothyroidism and in six patients the anti- dsDNA autoantibodies normalized despite continuing therapy. Although a significant number of patients developed autoantibodies against dsDNA, overt autoimmune disease related to these antibodies is a rare event and many patients spontaneously normalize these titres despite continuing IFN-alpha treatment.      

Autoimmunity against the β2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome

Complex regional pain syndrome (CRPS) is a painful condition affecting one or more extremities of the body, marked by a wide variety of symptoms and signs that are often difficult to manage because the pathophysiology is incompletely understood. Thus, diverse treatments might be ineffective. A recent report revealed the presence of autoantibodies against differentiated autonomic neurons in CRPS patients. However, it remained unclear how the antibodies act in the development of CRPS. We therefore aimed to characterize these antibodies and identify target antigens. Functional properties of affinity-purified immunoglobulin G of control subjects or CRPS patients were assessed using a cardiomyocyte bioassay. Putative corresponding receptors were identified using antagonistic drugs, and synthesized peptide sequences corresponding to segments of these receptors were used to identify the target epitopes. Chinese hamster ovary cells were transfected with putative receptors to ensure observed binding. Further, changes in the intracellular Ca²⁺ concentration induced by agonistic immunoglobulin G were measured using the Ca²⁺-sensitive fluorescent dye fura-2 assay. Herein, we demonstrate the presence of autoantibodies in a subset of CRPS patients with agonistic-like properties on the β₂ adrenergic receptor and/or the muscarinic-2 receptor. We identified these autoantibodies as immunoglobulin G directed against peptide sequences from the second extracellular loop of these receptors. The identification of functionally active autoantibodies in serum samples from CRPS patients supports an autoimmune pathogenesis of CRPS. Thus, our findings contribute to the further understanding of this disease, could help in the diagnosis in future, and encourage new treatment strategies focusing on the immune system.     

Autoimmune complications of COVID-19 and potential consequences for long-lasting disease syndromes

The latest WHO report determined the increasing diversity within the CoV-2 omicron and its descendent lineages. Some heavily mutated offshoots of BA.5 and BA.2, such as BA.4.6, BF.7, BQ.1.1, and BA.2.75, are responsible for about 20% of infections and are spreading rapidly in multiple countries. It is a sign that Omicron subvariants are now developing a capacity to be more immune escaping and may contribute to a new wave of COVID-19. Covid-19 infections often induce many alterations in human physiological defense and the natural control systems, with exacerbated activation of the inflammatory and homeostatic response, as for any infectious diseases. Severe activation of the early phase of hemostatic components, often occurs, leading to thrombotic complications and often contributing to a lethal outcome selectively in certain populations. Development of autoimmune complications increases the disease burden and lowers its prognosis. While the true mechanism still remains unclear, it is believed to mainly be related to the host autoimmune responses as demonstrated, only in some patients suffering from the presence of autoantibodies that worsens the disease evolution. In fact in some studies the development of autoantibodies to angiotensin converting enzyme 2 (ACE2) was identified, and in other studies autoantibodies, thought to be targeting interferon or binding to annexin A1, or autoantibodies to phospholipids were seen. Moreover, the occurrence of autoimmune heparin induced thrombocytopenia has also been described in infected patients treated with heparin for controlling thrombogenicity. This commentary focuses on the presence of various autoantibodies reported so far in Covid-19 diseases, exploring their association with the disease course and the durability of some related symptoms. Attempts are also made to further analyze the potential mechanism of actions and link the presence of antibodies with pathological complications.     

Additional autoimmune disease found in 33% of patients at type 1 diabetes onset

OBJECTIVE

We sought to define the prevalence of nonislet, organ-specific autoantibodies at diagnosis of type 1 diabetes and to determine the prevalence of comorbid autoimmune diseases.

RESEARCH DESIGN AND METHODS

Children (n = 491) diagnosed with type 1 diabetes at the Barbara Davis Center for Childhood Diabetes were screened for autoimmune thyroid disease (thyroid peroxidase autoantibodies [TPOAb]), celiac disease (tissue transglutaminase autoantibodies [TTGAb]), and Addison disease (21-hydroxylase autoantibodies [21OHAb]).

RESULTS

Of the 491 children, 161 had at least one nonislet autoantibody, and of these, 122 (24.8%) were positive for TPOAb, and 15 of the 122 (12.3%) had autoimmune thyroid disease. There were 57 (11.6%) who were positive for TTGAb, of whom 14 (24.6%) had celiac disease. Five (1.0%) were positive for 21OHAb, of whom one had Addison disease.

CONCLUSIONS

Many autoantibody-positive subjects present with additional autoimmune disorders. Detection of these autoantibodies at type 1 diabetes onset may prevent complications associated with delayed diagnosis of these disorders.Type 1 diabetes occurs in one in 300 individuals (1) and is associated with other autoimmune diseases, including autoimmune thyroid disease (AIT) in 15–30%, celiac disease (CD) in 4–9%, and Addison disease (AD) in 0.5% (2); detection of which is crucial to prevent morbidity related to unrecognized disease. Assays for thyroid peroxidase autoantibodies (TPOAb) in AIT, tissue transglutaminase autoantibodies (TTGAb) in CD, and 21-hydroxylase autoantibodies (21OHAb) in AD, may be used to screen for asymptomatic disease to identify risk of progression to overt disease. Previous studies have examined multiple autoantibodies in cohorts of patients with type 1 diabetes (3). We sought to define the prevalence of nonislet, organ-specific autoantibodies at the diagnosis of type 1 diabetes and to determine the prevalence of comorbid autoimmune diseases.     

Passive transfer of autoimmune disease with isologous IgG1 and IgG2 antibodies to the tubular basement membrane in strain XIII guinea pigs: loss of self-tolerance induced by autoantibodies

Initiation of an autoimmune tubulointerstitial disease was achieved in strain XIII guinea pigs by passive transfer of functionally pure IgG1 or IgG2 fractions of isologous anti-tubular basement membrane (TBM) serum. IgG2 appeared to be somewhat more effective than IgG1. The immunopathologic features in the IgG1 and IgG2 recipients were similar at the time of sacrifice, 14 days after transfer. The recipients that developed disease had higher than expected anti-TBM titers at 14 days. Furthermore, anti-TBM antibodies were of both IgG isotypes. In contrast, simultaneously administered IgG1 or IgG2 anti-BGG antibodies declined in titer in the recipients and were never found in the isotype fraction that had not been transferred. These findings indicate that the recipients of anti-TBM antibodies of either IgG1 or IgG2 isotype were stimulated to produce anti-TBM autoantibodies, which participated in the pathogenesis of the renal disease. The model demonstrates that autoantibodies may provide a mechanism (autoimmune amplification) for the intensification and perpetuation of antibody-mediated autoimmune diseases.     

Autoimmune thyroid disease: an integrated concept of Graves' and Hashimoto's diseases

Graves' disease and Hashimoto's thyroiditis have been previously considered separate clinical and pathologic entities. Current knowledge of the autoimmune cause of specific systemic syndromes has been applied to these seemingly dissimilar diseases and now permit evolution of a unified integrated concept for considering them as two subsets of a single pathologic process. Experimental and clinical data now support the thesis that autoimmune thyroid disease is a genetically conditioned immunologic dysfunction, perhaps an abnormality of suppressor lymphocytes that results in production of humoral and tissue antibodies directed against thyroid gland cells and receptors of other somatic tissues. Thyroid autoantibodies possess hormonally stimulatory qualities and cytotoxic (inflammatory or destructive) properties. They may be present singly or together in the same individual with resulting diverse clinical and biochemical patterns depending upon the predominance or concordance of specific antibodies. Further, antibodies in autoimmune thyroid disease may be directed against other somatic structures such as ocular muscle, skin, hair, pigment cells, hematologic organs, or other endocrine glands. The immune etiology appears to predispose to nonendocrine systemic autoimmune disorders that coincide with thyroid disease. It is not clear at this time how genetic factors influence the onset, course, or ultimate outcome of autoimmune thyroid disease or why certain associated immunopathies tend to cluster with one or the other of these syndromes. Our understanding of the immune etiology common to Graves' and Hashimoto's diseases permits a more precise definition of the terms hyperthyroidism and thyrotoxicosis, the former denoting a pathologic goitrous phenomenon and the latter, a peripheral tissue manifestation of cellular receptor site excess of thyroid hormones.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transplacentally transmitted autoimmune disorders of the fetus and newborn: pathogenic considerations.

Autoimmune diseases affect a significant number of women in their childbearing years. This group of disorders constitutes a heterogeneous spectrum with a common basis involving the presence of autoantibodies often of the IgG type. Transplacental transfer of autoantibodies is not uncommon, and autoantibodies can be readily demonstrated in newborn serum. Only a small proportion of infants with circulating autoantibodies exhibit clinical symptoms. The transient neonatal manifestations of maternal autoimmune disease disappear over a time course consistent with the catabolism of IgG, providing no permanent damage occurs. Thus the pathogenic role of transferred autoantibodies seems well established. However, maternal-autoantibody-mediated tissue damage appears to depend on factors other than the mere passage of the antibody to the fetal compartment. This review details putative factors that are likely to modulate the clinical expression of the fetal antigen-autoantibody reaction in offspring of mothers with autoimmune disorders. The importance of amount, type, and specificity of autoantibodies is described. The possible significance of fetal and maternal immunogenetics is briefly discussed, as well as the limited knowledge currently available on the fetal development of fetal antigenic sites at target organs. These and other as yet unidentified factors may help explain the rarity of clinical manifestations in infants exposed to potentially pathogenic maternal autoantibodies.     

Role of anti-C1q autoantibodies in the pathogenesis of lupus nephritis

Anti-C1q autoantibodies can be found in the sera of patients with several autoimmune diseases, but also in healthy individuals. Although these anti-C1q autoantibodies were already identified several decades ago, they still puzzle both immunologists and nephrologists. The main reason for this puzzling effect are observations that seemed to indicate quite clearly that anti-C1q should be pathogenic to the kidney and the observation on the other hand that anti-C1q autoantibodies can be found in several disease conditions, as well as in healthy individuals, and are then unrelated to overt renal inflammation. This puzzle is the focus of the current review, which will provide an overview of the historical data, define the clinical interests and, importantly, will try to put several aspects in perspective based on recent observations in patients and in murine models. In addition, the paper will discuss therapeutic intervention possibilities regarding anti-C1q-mediated damage in systemic lupus erythematosus, as well as the therapeutic potential of anti-C1q antibodies in other conditions.     

Autoimmune bullous disorders.

Bullous skin diseases represent a group of organ-specific autoimmune disorders characterised by binding of circulating autoantibodies to adhesion molecules of the epidermis and the dermo-epidermal basement membrane zone. Binding of these autoantibodies to their antigenic targets results in loss of adhesion between epidermal keratinocytes and at the level of the basement membrane zone. Chronic blisters and secondary painful erosions are the clinical hallmark of autoimmune bullous disorders. Histopathology reveals the location of blister formation and helps to classify the subtype of the bullous skin disorder. Immunofluorescence is crucial for diagnosing autoimmune bullous skin disorders. Tissue-bound autoantibodies are detected by direct immunofluorescence of perilesional skin. Circulating autoantibodies can be visualised by indirect immunofluorescence using tissue substrates such as monkey oesophagus and sodium chloride-split human skin. Most of the autoantigens are available as recombinant proteins, which allows for autoantibody screening by ELISA or immunoblot analysis to confirm the primary diagnosis and, importantly, for immunoserological follow-up of patients.     

Possible therapeutic applications of single-chain antibodies in systemic autoimmune diseases

B cells participate in the induction and maintenance of systemic autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, via production of pathogenic autoantibodies, contributing to the formation of immune complexes. Immune complex deposition in the kidney and joints causes inflammation and organ destruction, and chemokine production enhances T cell activation and tissue damage. The development of the disorder depends on several factors, for example, genetic susceptibility, environmental factors or immune dysregulation. Traditional therapies, which aimed at the alleviation of symptoms, are giving way to biological therapies with the potential of disrupting disease progression. This article focuses on antibody therapies, especially on the applications of single-chain antibodies, as new biological agents for the treatment of systemic autoimmune disorders.     

Disease association, origin, and clinical relevance of autoantibodies to the glycolytic enzyme enolase.

Serum autoantibodies to the glycolytic enzyme enolase have been reported in a diverse range of inflammatory, degenerative, and psychiatric disorders. Diseases in which these antibodies have been reported in high incidence include autoimmune polyglandular syndrome type 1 (80%, 35 of 44), primary (69%, 60 of 87), and secondary (58%, 14 of 24) membranous nephropathy, cancer-associated retinopathy (68.8%, 11 of 16), autoimmune hepatitis type 1 (60%, 12 of 20), mixed cryoglobulinemia with renal involvement (63.6%, seven of 11), cystoid macular edema (60%, six of 10), and endometriosis (50%, 21 of 41). In autoimmune polyglandular syndrome type 1 patients, all had chronic mucocutaneous candidiasis with demonstrated antibody reactivity to candida enolase, which is suggestive of cross reactivity or epitope mimicry. Formation of autoantibodies to enolase may be a normal process, with reported incidence in apparently healthy subjects ranging from 0% (zero of 91) to 11.7% (seven of 60). Nonetheless, we suggest that excessive production of these autoantibodies, which are generated as a consequence of uptake of enolase by antigen-presenting cells and subsequent B cell activation, can potentially initiate tissue injury as a result of immune complex deposition.