Development Of Autoimmune Pathology Research Articles

The type 1 diabetes susceptibility locus Idd5 favours robust neonatal development of highly autoreactive regulatory T cells in the NOD mouse.

Regulatory T lymphocytes expressing the transcription factor Foxp3 (Tregs) play an important role in the prevention of autoimmune diseases and other immunopathologies. Aberrations in Treg-mediated immunosuppression are therefore thought to be involved in the development of autoimmune pathologies, but few have been documented. Recent reports indicated a central role for Tregs developing during the neonatal period in the prevention of autoimmune pathology. We therefore investigated the development of Tregs in neonatal NOD mice, an important animal model for autoimmune type 1 diabetes. Surprisingly, we found that, as compared with seven other commonly studied inbred mouse strains, in neonatal NOD mice, exceptionally large proportions of developing Tregs express high levels of GITR and PD-1. The latter phenotype was previously associated with high Treg autoreactivity in C57BL/6 mice, which we here confirm for NOD animals. The proportions of newly developing GITRhighPD-1+ Tregs rapidly drop during the first week of age. A genome-wide genetic screen indicated the involvement of several diabetes susceptibility loci in this trait. Analysis of a congenic mouse strain confirmed that Idd5 contributes to the genetic control of GITRhighPD-1+ Treg development in neonates. Our data thus demonstrate an intriguing and paradoxical correlation between an idiosyncrasy in Treg development in NOD mice and their susceptibility to type 1 diabetes.

Sarcoidosis-related autoimmune inflammation in COVID-19 convalescent patients.

Currently, there are a large number of reports about the development of autoimmune conditions after COVID-19. Also, there have been cases of sarcoid-like granulomas in convalescents as a part of the post-COVID-19 syndrome. Since one of the etiological theories of sarcoidosis considers it to be an autoimmune disease, we decided to study changes in the adaptive humoral immune response in sarcoidosis and SARS-CoV-2 infection and to find out whether COVID-19 can provoke the development of sarcoidosis. This review discusses histological changes in lymphoid organs in sarcoidosis and COVID-19, changes in B cell subpopulations, T-follicular helper cells (Tfh), and T-follicular regulatory cells (Tfr), and analyzes various autoantibodies detected in these pathologies. Based on the data studied, we concluded that SARS-CoV-2 infection may cause the development of autoimmune pathologies, in particular contributing to the onset of sarcoidosis in convalescents.

The Frequency of Intrathyroidal Follicular Helper T Cells Varies with the Progression of Graves' Disease and Hashimoto's Thyroiditis.

Objective Autoimmune thyroid diseases (AITD), mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common organ-specific autoimmune diseases characterized by circulating antibodies and lymphocyte infiltration. Follicular helper T (Tfh) cell dysregulation is involved in the development of autoimmune pathologies. We aimed to explore the role of intrathyroidal and circulating Tfh cells in patients with GD and HT. Methods Ultrasound-guided thyroid fine-needle aspiration (FNA) was conducted in 35 patients with GD, 40 patients with HT, and 22 patients with nonautoimmune thyroid disease (nAITD). Peripheral blood samples were also obtained from 40 patients with GD, 40 patients with HT, and 40 healthy controls. The frequencies of intrathyroidal and circulating Tfh cells from FNA and peripheral blood samples were assessed by flow cytometry. Additionally, the correlations between the frequencies of the Tfh cells and the levels of autoantibodies and hormones or disease duration were analyzed. Results The frequency of intrathyroidal CD4+CXCR5+ICOShigh Tfh cells was higher in HT patients than in GD patients. Significant correlations were identified between the percentages of circulating and intrathyroidal Tfh cells and the serum concentrations of thyroid autoantibodies, especially thyroglobulin antibodies (TgAb), in AITD. Intrathyroidal CD4+CXCR5+ICOShigh Tfh cells were positively correlated with free triiodothyronine (FT3) in HT patients but negatively correlated with FT3 in GD patients. In addition, HT patients with a longer disease duration had an increased frequency of intrathyroidal CD4+CXCR5+ICOShigh and CD4+CXCR5+PD-1+ Tfh cells. In contrast, in the GD patients, a longer disease duration did not affect the frequency of intrathyroidal CD4+CXCR5+ICOShigh but was associated with a lower frequency of CD4+CXCR5+PD-1+ Tfh cells. Conclusions Our data suggest that intrathyroidal Tfh cells might play a role in the pathogenesis of AITD and they are potential immunobiomarkers for AITD.

Antithyroid autoantibodies in extrathyroid autoimmune diseases

This review summarizes data on the incidence of autoimmune diseases and examines the prevalence of antithyroid antibodies in extrathyroid autoimmune diseases. In the world, about 5–7% of the population suffers from one or another type of autoimmune diseases. Among the six most common autoimmune diseases, thyroid and associated diseases predominate. The high prevalence of autoimmune thyroid diseases raises questions about the potential role of antithyroid antibodies in the course of extrathyroid autoimmune diseases. It is believed that autoimmune diseases are the result of interactions between triggers, autoantigens, genetic predisposition, impaired tolerance of autoantigens and mechanisms of apoptosis. Among the currently known antithyroid autoantibodies, antibodies to thyroglobulin (TgAb), thyroid peroxidase (TPO), as well as bispecific autoantibodies to thyroglobulin and thyroid peroxidase are of particular importance. Categories of functionally significant autoantibodies that mimic hormone function and provoke the development of autoimmune pathology as a result of binding to the receptor and subsequent stimulation of thyrocytes include antibodies to thyroid-stimulating hormone receptor (rTSH-Ab). Circulating antibodies against thyroid antigens are not limited to autoimmune diseases of the thyroid gland, but are also found in other autoimmune diseases, most often in rheumatoid arthritis, type 1 diabetes mellitus and celiac disease. The association with other immune pathologies further confirms that TPO antibodies were also detected in 15% of patients with asthma, in 10–29% of those with idiopathic purpura and vitiligo. The prevalence of TPO antibodies is slightly higher than TgAb, and rTSH-Ab are rarely registered in non-thyroid immunological diseases.

AUTOIMMUNE MARKERS IN MEASLES INFECTION OF VARYING SEVERITY

Measles is an acute viral infectious disease caused by an RNA-containing virus of Morbilliviridae genus. This infectious disease is characterized by the development of catarrhal syndrome, general intoxication syndrome and specific exanthema. The virus is transmitted from person to person by airborne mechanism, when coughing, sneezing and exhaling air droplets during conversation. It is shown that measles is characterized by long-term immunosuppression, which persists for a long period after the patient's clinical recovery and normalization of blood parameters that can lead to an exacerbation of various chronic and autoimmune diseases. Taking into account the impairment of cytokine and immunological reactivity observed in adult patients with measles infection, violations of the dynamics of interferon levels elevation and immunosuppression caused by the virus itself, as well as the lack of studies on autoantibody levels in patients with measles of varying severity, investigating autoimmune markers is of great relevance as can be used to predict and prevent the development and activation of autoimmune responses. The purpose of the study is to determine the involvement of autoimmune reactions in the immunopathogenesis of measles infection in individuals with various degrees of severity of the disease. The study included 65 patients with a diagnosis of measles who were treated at the Kharkiv region clinical infectious hospital in the period for 2017 – 2019. Depending on the severity of the disease and the presence of complications the patients included in the study were divided into 4 groups. The control group consisted of 20 voluntary donors who at the time of blood sampling had no clinical signs of measles, had no contact with infected patients, and had no exclusion criteria.
 All patients included in the study were tested for serum levels of antibodies to cell membrane phospholipids, IgG to liver and kidney microsomes (anti-LKM-1), and IgG to native DNA (ADNA 2) on the 1st and 10th day of hospital stay. These indicators were assessed by the method of solid-phase enzyme immunoassay (ELISA) using test systems manufactured by “Granum” LLC (Ukraine), EUROIMMUNE (Germany) and BioRad (USA). Statistical processing of the obtained results was carried out using the Statistica 6.0 software. When interpreting the significance of the difference in results, the Student's criterion was used; the critical value of the significance level was considered to be p ˂ 0.05. Results and discussion. It was found that on the day of admission to the hospital there was an increase in the level of autoantibodies to native DNA, liver and kidney microsomes, as well as cell membrane phospholipids in all groups of patients. In dynamics (on the 10th day of hospital stay), the patients of groups 1-4 demonstrated a decrease in the level of all types of autoantibodies; in the patients who had a severe course of the disease and developed complications development, the levels was higher than in the control group. The obtained data indicate that with the development of measles infection against the background of activation of general and specific immune response, there is an activation of autoimmune reactions, whose activity fades as the infectious process goes away. Autoimmune reactions under a favourable clinical course of measles infection, most likely, are not aggressive but protective by their nature and are aimed at eliminating infected and damaged cells. Patients with measles of varying severity have increased levels of autoantibodies to native DNA, liver and kidney microsomes, as well as cell membrane phospholipids. It has been found out that the levels of autoantibodies do not go beyond the reference values, but in severe disease, borderline values of autoantibodies are recorded in a significant number of patients. The study of autoantibody levels can be recommended in cases of severe measles infection, both with and without complications, to predict and prevent the development of autoimmune pathology.

CONDITION OF HUMORAL IMMUNITY IN PATIENTS WITH SYSTEMIC DISEASES OF CONNECTIVE TISSUE WITH ACTIVATED CHRONIC SIMPLE HERPETIC INFECTION

The aim - to study and to analyze the indicators of the humoral link of the immune system in patients with systemic connective tissue diseases with chronic activated HSV 1/2 infection and to assess the effect of the revealed disorders on the development of autoimmune pathology.
 Materials and methods. We examined 380 patients with systemic diseases of the connective tissue (systemic lupus erythematosus, systemic vasculitis, rheumatoid arthritis, psoriasis) with chronic HSV 1/2 infection at the age of 21-67 years. In 45 of them, using the modern molecular genetic diagnosis of herpes simplex, the active phase of chronic HSV 1/2 infection was verified based on the results of the polymerase chain reaction, and in the other 335, the latent phase was verified. The control group consisted of 20 healthy individuals of the appropriate age and gender. In patients with systemic connective tissue diseases with chronic HSV 1/2 infection, the humoral immunity indices were studied: levels of complement component C3 and IFN-a in saliva and blood and acquired: concentration of common major immunoglobulinins: IgG, IgM IgA, IgE; specific IgM and IgG to HSV 1/2; levels of cryoglobulins, cryofibrinogen, CІC in serum. Statistical processing of the results of the study was carried out using generally accepted methods of variation statistics.
 Results. In patients with systemic diseases of connective tissue with chronic HSV 1/2 infection, activation of the humoral immunity was detected, it was especially evident in the active phase of the infection and was characterized by an increase in the antibody production of specific IgM HSV 1/2 and IgG HSV 1/2, аn increase in the levels of CIC, IgM, IgA and IgE, cryoprecipitation proteins, IFN-a in the blood. In the latent phase of HSV 1/2 infection the levels of IgG production of HSV 1/2, IgE, CEC, cryofibrinogen and cryoglobulins in the blood serum of these patients increased.
 Conclusions. The presence of chronic activated HSV 1/2 infection in patients with systemic diseases of the connective tissue causes activation of the humoral immunity, creates the conditions for the development of autoimmune processes.

Peculiarities of cellular immunity in patients with systemic connective tissue diseases with chronic activated herpes simplex virus infection

The formation of an immune response in patients with systemic connective tissue diseases with chronic activated HSV infection is a complex and multicomponent process, that determines the state of innate and acquired cellular immunity, which is largely predetermined to the nature of the course of this infection and the intensity of its activation. Objective. Detect changes in indicators of the cellular level of immunity in patients with systemic connective tissue diseases with chronic activated HSV ½ infection and evaluate the impact of these disorders on the development of autoimmune pathology. Material and methods. 380 patients with systemic connective tissue diseases (systemic lupus erythematosus, systemic vasculitis, rheumatoid arthritis, psoriasis) with chronic HSV ½ infection were examined. In 45 of them, based on the results of the polymerase chain reaction, the active phase of chronic HSV ½ infection was verified, while in the other 335, the latent phase. To assess the state of innate cellular immunity was determined phagocytic indices, using the stimulating activity of E.coli cells. The state of acquired cellular immune surveillance was studied on the basis of an analysis of the results of the quantitative composition of the populations and subpopulations of lymphocytes, their functional capacity for the expression of early and late activation markers. Statistical processing of the results of the study was carried out using generally accepted methods of variation statistics. Results. In patients with systemic connective tissue diseases with chronic activated HSV ½ infection have revealed activation of the cellular immune system, especially in the active phase of HSV ½, which confirms the existence of immune-dependent processes with increased autoaggression and attenuated anti-infective immune protection during reactivation. Conclusions. The presence of chronic activated HSV ½ infection in patients with systemic connective tissue diseases causes activation of cellular immunity, which creates the conditions for the development of autoimmune processes.

Vitamin D and neurospecific proteins in children with inflammatory demyelinating diseases of central nervous system

The relevance of studying the provision of vitamin D in children with inflammatory diseases of the central nervous system (CNS) is due to a high prevalence of vitamin D deficiency conditions in children population, which, according to current literature data, leads to the imbalance of the immune system and a predisposition to a severe disease course, chronization of the process, development of autoimmune pathology. The study of the concentration of neurospecific proteins (NSP) in blood serum and cerebrospinal fluid (CSF) has been recently used to analyze the degree and nature of nervous tissue damage in case of various CNS diseases. The study included investigation of blood serum and CSF samples obtained from 107 children (34 – with encephalitis, 28 – with disseminated encephalomyelitis (DEM), 20 – with multiple sclerosis (MS), 25 – control group). Determination of vitamin D levels (25(OH)D) was performed by the method of electrochemiluminescence immunoassay, concentrations of myelin basic protein, neuron-specific enolase, S100 protein and glial fibrillary acidic protein – by ELISA method. A decrease in the concentration of vitamin D under 30 ng/ml was found in 95% of children with inflammatory diseases of the central nervous system, while the severity of the deficiency of 25(OH)D was associated with the severity of the disease course. In the early stages of the disease in all groups, a significant increase in the level of the main myelin protein was found, while an increase in the concentration of other NSP was observed less frequently and was associated with a severe and complicated course of the disease. Correlations of different intensity and direction between NSP and 25(OH)D were found, which indicates their importance in the pathogenesis of inflammatory diseases of CNS.

MECHANISMS OF IMMUNOLOGICAL TOLERANCE DISRUPTION

Autoimmune diseases belong to disorders with an unclear etiology. The spectrum of autoimmune diseases is wide, the most well known of them are type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn’s disease, vitiligo, and others. The key role in the development of autoimmune reactions is played by disturbances of immunological homeostasis. Despite numerous researches, the exact mechanisms of autoimmunity still remain unclear. The analysis of data provided by the literature on the mechanisms of disorders of immunological tolerance is presented in the review. The most discussed theories of pathological autoimmune processes development are described: the theory of hereditary predisposition, the theory of immunological dysregulation and regulatory T-cell dysfunction, the theory of network regulation, the infectious theory of autoimmune diseases development (molecular mimicry, polyclonal activation of lymphocytes). The theory of hereditary predisposition reflects the critical role of hereditary factors in the development of autoimmunity, in particular, the data on relations of autoimmune disorders to human major histocompatibility complex are provided. In addition, the data indicating that the development of autoimmune processes in an organism can be associated with changes in the content and function of regulatory T-lymphocytes are provided in the work. These cells are directly involved in the mechanisms of cellular immune responses in autoimmune diseases and may explain the disorders of immunological tolerance, subsequently leading to the development and progression of immunopathology. The idea of idiotype-anti-idiotype interactions, which can serve as a mechanism ensuring normal autoimmune reactions or lead to the activation of autoreactive clones, is revealed in the description of network regulation theory. The infectious theory of development of autoimmune pathologies presented in the review is based on the results of numerous researches and suggests that the viruses can provoke failures of immunity and lead to autoimmunity.

Plasmacytoid dendritic cells: Key players in viral infections and autoimmune diseases

ObjectiveDescribe the main activation and inhibitory pathways and receptors by which pDC regulate type I interferon secretion, as well as its association with autoimmune pathology. MethodsA PubMed search for articles was conducted using the following key words: plasmacytoid dendritic cells, autoimmune diseases, viral infections and type I interferon. The search was limited to publications in English and from 1957 to 2012. Sixty-five of these articles are included in this review. The most relevant primary research articles identified were critically evaluated and compiled together. Particularly, areas of consensus and controversy were identified and analyzed. ResultsPlasmacytoid dendritic cells have been closely related to viral infections and autoimmune disease, mainly because of these immune cells are able to secrete large amounts of type I interferon. This function is linked with their expression of Toll-like receptors, specially TLR7 and TLR9, which are designed to sense nucleic acids in the early endosomes. Activated pDC can promote immunity and autoimmunity, however, the exact mechanisms by which pDC promote one vs. the other are not well understood. ConclusionsPlasmacytoid dendritic cells play a key role in both, immunity and autoimmunity. Current evidence suggests that the sustained overproduction of type-I interferon drives aberrant immune responses and the development of autoimmune pathology.

The development and function of follicular helper T cells in immune responses

Follicular helper T cells (Tfh) have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.

An IL15-dependent novel immune cell subset with multiple functionalities affecting the onset and severity of autoimmune disease (171.36)

Abstract Interferon-producing killer dendritic cells (IKDC) are a recently discovered innate cell subset that shares morphological and functional characteristics of NK and DC cells. The aim of this study is to investigate the role of IKDCs in terms of initiating autoimmune disease. We found that these cells are expanded in mice with multiple copies of the TLR7 gene and that the number of these cells correlates with disease activity. Expansion of this population is due to their cell intrinsic sensitivity to TLR7 stimulation. IKDCs are dependent of IL15, produce high levels of IFN type I and type II after stimulation with a TLR7 agonist, are capable of MHC class II antigen presentation, and can cross-present antigen to CD8 cells. Adoptive transfer of IKDC to wild type mice causes activation of naïve T cells, expansion of inflammatory monocyte populations and IFN-dependent CD8 activation. IKDC adoptive transfer also induces elevated inflammatory cytokine and IgG levels in the serum. We found that IFN type I and CD40/CD40L interactions are essential for the inflammatory effect of these cells. Taken together these results uncover a potential role for this cell populaiton in the development of autoimmune pathologies.

Altered frequency and phenotype of CD4+ forkhead box protein 3+ T cells and its association with autoantibody production in human immunodeficiency virus-infected paediatric patients.

The association between immune dysfunction and the development of autoimmune pathology in patients with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is not clear. The frequency and phenotype of regulatory T cells, as well as the presence of autoantibodies, were evaluated in a paediatric cohort of HIV-infected patients without clinical evidence of autoimmune disease. Lower absolute counts but higher percentages of total CD4(+) forkhead box protein 3 (FoxP3)(+) T cells were recorded in children with severe immunosuppression than in those without evidence of immunosuppression. The frequencies of classical CD4(+) CD25(+) FoxP3(+) regulatory T cells were not altered, whereas CD4(+) FoxP3(+) CD25(-) T cells were found increased significantly in patients with severe immunosuppression. Like classical regulatory T cells, CD4(+) FoxP3(+) CD25(-) T cells display higher cytotoxic T-lymphocyte antigen 4 (CTLA-4) but lower CD127 expression compared with CD4(+) FoxP3(-) CD25(+) T cells. An improvement in CD4(+) T cell counts, along with a decrease in viral load, was associated with a decrease in CD4(+) FoxP3(+) CD25(-) T cells. The majority of the patients with severe immunosuppression were positive for at least one out of seven autoantibodies tested and displayed hypergammaglobulinaemia. Conversely, HIV-infected children without evidence of immunosuppression had lower levels of autoantibodies and total immunoglobulins. A decline in CD4(+) FoxP3(+) T cell numbers or a variation in their phenotype may induce a raise in antigen exposure with polyclonal B cell activation, probably contributing to the generation of autoantibodies in the absence of clinical autoimmune disease.

Risk allele frequencies of several genes controlling the development of autoimmune pathologies in the population of belarus

The population genotype and allele frequencies of +49A/G of the cytotoxic T-lymphocyte antigen 4 gene (CTLA4); −1858C/T of the protein tyrosine phosphatase gene (PTPN22); and −23HphIA/T of the insulin gene (INS) were detected in ethnic Belarusians from six ethnogeographical regions. Frequencies of the risk allele homozygous carriers were 17.3% for the CTLA4 gene +49G, 50.7% for the insulin gene −23HphIA, and 4.1 for the PTPN22 gene −1858T. The homozygous risk genotype of all three loci was detected in five individuals of 662 individuals tested; the homozygous combination of protective alleles was detected in 21 individuals. The similarity in the allele and genotype distribution of the studied loci on the territory of Belarus was demonstrated.

Endosulfan increases seric interleukin-2 like (IL-2L) factor and immunoglobulin M (IgM) of Nile tilapia ( Oreochromis niloticus) challenged with Aeromona hydrophila

Endosulfan is a persistent organochlorine insecticide which is extremely toxic to fish. It is known to induce immunological alterations in juvenile Nile tilapia ( Oreochromis niloticus) such as increases in phagocytic activity and reactive oxygen species production of spleen macrophages. The purpose of the present study was to demonstrate the effects of acute exposure to a sublethal concentration of endosulfan (7 ppb, 96 h) on parameters of the adaptive humoral immune response of the aforementioned aquatic organism. The effect of endosulfan on the capacity of immune cells to produce interleukin-2 like (IL-2L) factor and immunoglobulin M (IgM) in response to a challenge with ½ LD50 of the infectious bacteria Aeromonas hydrophila was evaluated. Experimental results indicate that short, sublethal, endosulfan exposure triggers a succession of events beginning with non-specific activation of macrophages followed by an exacerbated synthesis of the IL-2L factor by activated B cells. This leads to significantly increased secretion of IgM and could in turn facilitate autoantibody production and the development of autoimmune pathologies.

Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice

Dysregulated innate responses, particularly excessive activation of interferon (IFN) pathways, have been implicated in the development of autoimmune pathologies. Autoreactivity frequently targets IFN-inducible genes such as the Ro autoantigens, which ubiquitinate and inhibit interferon regulatory factors (IRFs). A new study validates the role of these common autoantigens in preventing autoimmunity. The findings reveal that injury-induced systemic autoimmune disease is exacerbated in the absence of Ro52/Trim21 and is driven by the IL-23–Th17 pathway.

Impaired Maturation and Survival of T Lymphocytes, B Lymphocytes, and NK Cells in Mice Lacking Gimap5/Ian5.

In biobreeding rats (BB), the lyp mutation in Gimap5/Ian5 is associated with T-cell lymphopenia and autoimmune insulinitis. To delineate the role of Gimap5 in peripheral T cell survival, we generated Gimap5-deficient mice by targeted disruption. Gimap5−/− mice are viable to adulthood, but develop fulminant autoimmune hepatitis, become moribund, and die at a median age of 12 weeks. Gimap5−/− mice are lymphopenic, displaying an overall 7-fold reduction in peripheral T cells and a 43-fold reduction in peripheral CD8+ T cells. Additionally, Gimap5−/− mice exhibit an early, complete block in both NK and NKT lineage development and a partial block in B cell commitment to T1, T2, and mature subsets. Data from lethally irradiated congenic strains reconstituted with Gimap5−/− bone marrow will also be presented. Taken together, these data indicate that Gimap5 is necessary for peripheral survival of T lymphocytes and development of B lymphocytes and NK cells. Furthermore, these data suggest that Gimap5 deficiency plays a role in the development of autoimmune pathology in the mouse.

An appraisal of T cell subsets and the potential for autoimmune injury

The initiation of T cell dependent immune responses requires the T cell to utilize a heterodimeric cell surface antigen receptor to recognize an antigenic peptide in association with major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells (APCs). This is a necessary but insufficient signal for T cell activation. T cells must additionally receive a costimulatory signal that can be delivered through a variety of receptor-ligand pairs. Of these, the best characterized is the CD28-B7 (CD80 and CD86) couple. It has been appreciated for decades that the outcome of the T cell-APC interaction is highly variable and can lead to different forms of immune responses. The past decade has witnessed major advances in the definition of how distinct lymphocyte functions are dictated by expression of distinct cytokines, activation of defined signal transduction pathways, and, most recently, expression of distinct transcription factors. The production of ever increasing numbers of induced mutant mouse strains has created new reagents in which to analyze the role of particular cytokines or other proteins in defined immune responses. While the temptation remains to accomodate emerging information into reductionist models of T cell dependent immunopathology, it is our view that in vivo immune responses are highly complex and regulated events that defy simple categorization.

Alleviation of autoimmune disease in MRL-lpr mice by administration of Ye19.1, a monoclonal specific for the lpr T cell antigen, LTA

The MRL-lpr murine model of systemic lupus erythematosus (SLE) has provided many insights into the pathology of human lupus. The model is characterized by an age-dependent expansion of a Thy-1 + αβ CD3 + CD4 −, CD8 − T-cell subset in the nodes and spleen. In this study, a lpr T-cell specific monoclonal antibody, Ye19.1, was found to bind to a 200 kDa cell surface molecule (termed LTA) which has a phosphotyrosine phosphatase (PTPase) enzymatic function. The significance of this marker in the development of autoimmune pathology in MRL lpr mice was also demonstrated; treatment of MRL-lpr mice with the Ye19.1 Ab was shown to retard the development of the autoimmune syndrome and to restore the T cell-dependent immune response to ovalbumin.