Genetic and immunological basis of autoimmune diabetes in the NOD mouse

The non-obese diabetic (NOD) mouse is an animal model of human insulin-dependent diabetes mellitus (IDDM). Most NOD mice show insulitis at several weeks of age, and 60-90% of the female mice develop overt diabetes after 20-30 weeks of age. NOD mice share many features of human IDDM. As in human IDDM, the disease development in NOD mice is controlled by a number of disease susceptibility or resistant genes (Idds), including the major histocompatibility complex locus. Cumulative evidence suggests that Thl CD4+ T cells play a critical role in the autoimmune process leading to beta cell destruction. In addition to CD4+ T cells, CD8+ cells and B cells also participate in the pathogenesis. There are several candidate antigens recognized by autoreactive T cells such as glutamic acid decarboxylase (GAD), insulin and heat shock protein (HSP) 60. Treatment by these antigens suppresses IDDM development in NOD mice, suggesting that they may initiate the autoimmune process of NOD mice.     

HLA-DQ association and allele competition in Chinese narcolepsy

In Japanese, Koreans and Caucasians, narcolepsy/hypocretin deficiency is tightly associated with the DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype. Studies in African-Americans suggest a primary effect of DQB1*06:02, but this observation has been difficult to confirm in other populations because of high linkage disequilibrium between DRB1*15:01/3 and DQB1*06:02 in most populations. In this study, we studied human leucocyte antigen (HLA) class II in 202 Chinese narcolepsy patients (11% from South China) and found all patients to be DQB1*06:02 positive. Comparing cases with 103 unselected controls, and 110 and 79 controls selected for the presence of DQB1*06:02 and DRB1*15:01, we found that the presence of DQB1*06:02 and not DRB1*15:01 was associated with narcolepsy. In particular, Southern Chinese haplotypes such as the DRB1*15:01-DQA1*01:02-DQB1*06:01 and DRB1*15:01-DQA1*01:02-DQB1*05 were not associated with narcolepsy. As reported in Japanese, Koreans, African-Americans and Caucasians, additional protective effects of DQA1*01 (non-DQA1*01:02) and susceptibility effects of DQB1*03:01 were observed. These results illustrate the extraordinary conservation of HLA class II effects in narcolepsy across populations and show that DRB1*15:01 has no effect on narcolepsy susceptibility in the absence of DQB1*06:02. The results are also in line with a previously proposed 'HLA-DQ allelic competition model' that involves competition between non-DQA1*01:02, non-DQB1*06:02 'competent' (able to dimerize together) DQ1 alleles and the major DQα*01:02/ DQβ*06:02 narcolepsy heterodimer to reduce susceptibility.     

Pandemic and seasonal human influenza virus infections in domestic cats: prevalence, association with respiratory disease, and seasonality patterns

Domestic cats have several features that make them ideal vehicles for interspecies transmission of influenza viruses; however, they have been largely overlooked as potential reservoirs or bridging hosts. In this study, we conducted serological surveillance to assess the prevalence of novel pandemic H1N1 as well as seasonal human influenza virus infections in domestic cats in Ohio. Four hundred serum samples collected from domestic cats (September 2009 to September 2010) were tested using a hemagglutination inhibition (HI) test. The seroprevalences of pandemic H1N1, seasonal H1N1, and H3N2 were 22.5%, 33%, and 43.5%, respectively. In addition, a significant association between clinical feline respiratory disease and influenza virus infection was documented. In this sample of cats, the prevalence of pandemic H1N1 did not follow the seasonality pattern of seasonal H1N1 or H3N2 influenza, similar to observations in humans. Pandemic H1N1 seroprevalence did not vary in relation to ambient temperature changes, while the seroprevalence of seasonal H3N2 and H1N1 influenza viruses increased with the decline of ambient temperature. Our results highlight the high prevalence of influenza virus infection in domestic cats, a seasonality pattern of influenza virus infection comparable to that in humans, and an association of infection with clinical respiratory disease.     

HLA-DR2 association with excessive somnolence in narcolepsy does not generalize to sleep apnea and is not accompanied by systemic autoimmune abnormalities

Recent reports that nearly all patients with narcolepsy have the HLA-DR2 phenotype suggest that autoimmunity may underly the etiology or pathogenesis of this disorder. Of 11 narcoleptic patients in the present study, 9 were HLA-DR2, confirming the strong association with this class II antigen but indicating that this is not an obligatory phenotype. In contrast only 3/10 patients with sleep apnea were HLA-DR2, suggesting that this form of excessive somnolence has a different etiopathogenesis. Significant levels of rheumatoid factor, antinuclear antibodies or autoantibodies to native DNA, denatured DNA, histones, Sjogren's syndrome B antigen, or Smith antigen were undetectable in sera from narcoleptic patients. Antibodies to rodent brain, primate brain stem, and neurocytotoxic antibodies were also not found. These results along with the absence of laboratory signs and clinical features of a systemic inflammatory process indicate that if narcolepsy is an autoimmune disease, the underlying lesion or pathologic condition may be confined to the central nervous system.     

Genetic complexity of autoimmune myocarditis

Autoimmune myocarditis, a chronic stage of myocardial inflammation, occurs in a small subset of patients after acute cardiotropic viral infection and can lead to dilated cardiomyopathy (DCM). This disease can be recapitulated in susceptible mouse strains by infection with coxsackievirus B3, or by immunization with cardiac myosin or cardiac troponin I. The etiologies of myocarditis are multifactorial and genetically complex. Genetic linkage between susceptibility to myocarditis/DCM and the major histocompatibility complex (MHC) genes has been reported in both humans and experimentally induced mouse models. However, unlike other autoimmune diseases, the non-MHC genes seem to have greater impact than MHC genes on disease susceptibility. Several myocarditis-related non-MHC loci have been identified by our laboratory and others in different models. Most of these loci overlap with other autoimmune disease susceptibility loci, suggesting common or shared genetic traits influencing general autoimmunity. For example, we have demonstrated that Eam1 and Eam2 may influence disease susceptibility via regulating T cell apoptosis at different developmental stages. Blockade of signaling through specific genes, such as CTLA4, ICOS and PD-1, can either enhance or prevent the development of experimental autoimmune myocarditis, but it remains unclear whether functional polymorphisms in these genes are involved in predisposition to disease. In humans, mutations/deletions in immunologically important genes such as CD45, and genes encoding cardiac proteins, have been reported in patients with recurrent myocarditis or DCM. Identification of genetic polymorphisms controlling autoimmune myocarditis will help us understand the mechanisms underlying autoimmune diseases in general, thereby improving potential therapies in patients.     

Evaluating chronic urticaria patients for allergies,infections, or autoimmune disorders

Urticaria is a common disorder affecting one-fifth of the world's population. The pathophysiology is characterized by an increased propensity for mast cell degranulation with the release of potent mediators into the dermal and subdermal tissues with resulting vasoactive, chemotactic, and inflammatory effects. The final clinical manifestation of the typical urticarial lesion is the effect of several diverse effects and causes. The general classification is acute, chronic, and physical urticaria. In general, allergenic triggers can be identified in between 60–80% of acute urticarias. Physical urticarias are characterized by the onset after the specific inciting stimulus, which can reproduce the characteristic lesion which is usually of shorter duration (with the exception of delayed pressure urticaria). Chronic idiopathic urticaria is associated with thyroid autoimmunity and, more recently, anti-mast cell receptor antibodies. An extensive work-up is usually not indicated or helpful in identifying a cause. Food or other allergens are rare causes of this type of presentation. The evaluation and work-up is dependent on clues identified by history. The treatment is removal of specific and non-specific triggers and the use of symptomatic medications generally attenuating the mediator effects.     

The role of infections in autoimmune disease

Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.     

Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease

Virus infections and autoimmune disease have long been linked. These infections often precede the occurrence of inflammation in the target organ. Several mechanisms often used to explain the association of autoimmunity and virus infection are molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. These mechanisms have been used separately or in various combinations to account for the immunopathology observed at the site of infection and/or sites of autoimmune disease, such as the brain, heart, and pancreas. These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections.     

Cellular basis of T-cell autoreactivity in autoimmune diseases

There is no doubt that T cells play a key role in the pathogenesis of autoimmune diseases (AD) both as effector and regulatory cells. Despite spectacular progress in the understanding of natural tolerance to self, owing particularly to transgenic technology, important questions remain open regarding the pathogenesis of AD, the conditions favoring the transition from benign or ‘physiological’ autoimmunity to deleterious autoimmunity, and the precise effector mechanisms. This review on the cellular basis of T-cell-mediated AD begins with an enumeration of the main arguments in favor of direct T-cell involvement, special emphasis being given to two animal models which have been most extensively investigated: experimental allergic encephalomyelitis, and the nonobese diabetic mouse. The question as to whether pathogenic T cells use a restricted repertoire of Vβ genes is examined in the context of these two models. From here we proceed to an evaluation of the mechanisms of onset of AD, discussing both extrinsic and intrinsic factors responsible for the breakdown in T-cell tolerance and reviewing the arguments in favor of suppressor T cells being actively involved in the prevention of autoimmunity. The last two sections are devoted to the effector mechanisms responsible for tissue injury in organ-specific AD and to T-cell-directed therapeutic interventions, respectively. We discuss the two main pathogenic hypotheses based on direct intervention of cytotoxic T cells or indirect involvement of inflammatory cytokines and macrophages, and evaluate the importance of ecotaxis in leading autoreactive T cells to the site of injury. We conclude on a brief and nonexhaustive list of strategies aimed at selectively neutralizing potentially harmuful T cells.     

Genetic basis of murine lupus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the formation of a variety of autoantibodies and subsequent development of severe glomerulonephritis. Etiology of SLE remains unknown even if it is now well established that SLE is under polygenic control as well as the contribution of hormonal and environmental factors. The availability of several murine strains that spontaneously develop an autoimmune syndrome resembling human SLE, such as New Zealand, MRL and BXSB mice has provided useful tools for the genetic dissection of susceptibility to SLE. Moreover, development of various transgenic and mutant mice has made it possible to identify a number of susceptibility genes such as those involved in the regulation of apoptosis or B cell receptor signaling that can trigger lupus-like phenotypes. Obviously, further identification of the genetic defects present in lupus-prone mice is of paramount importance for understanding the immunopathogenesis of SLE.