Coeliac disease-specific autoantibodies targeted against transglutaminase 2 disturb angiogenesis

Coeliac disease is characterized by immunoglobulin-A (IgA)-class autoantibodies targeted against transglutaminase 2 (TG2), a multi-functional protein also with a role in angiogenesis. These antibodies are present in patient serum but are also found bound to TG2 below the epithelial basement membrane and around capillaries in the small intestinal mucosa. Based on these facts and the information that the mucosal vasculature of coeliac patients on a gluten-containing diet is disorganized, we studied whether the coeliac disease-specific autoantibodies targeted against TG2 would disturb angiogenesis. The effects of coeliac disease-specific autoantibodies on in vitro angiogenesis were studied in angiogenic cell cultures. The binding of the antibodies to cells, endothelial sprouting, migration of both endothelial and vascular mesenchymal cells, the integrity of the actin cytoskeleton in both cell types and the differentiation of vascular mesenchymal cells were recorded. In vitro, IgA derived from coeliac disease patients on a gluten-containing diet binds to surface TG2 on endothelial and vascular mesenchymal cells and this binding can be inhibited by the removal of TG2. In addition, coeliac disease-specific autoantibodies targeting TG2 disturb several steps of angiogenesis: endothelial sprouting and the migration of both endothelial and vascular mesenchymal cells. Furthermore, the autoantibodies cause disorganization of the actin cytoskeleton in both capillary cell types that account most probably for the defective cellular migration. We conclude that coeliac disease-specific autoantibodies recognizing TG2 inhibit angiogenesis in vitro. This disturbance of the angiogenic process could lead in vivo to the disruption of the mucosal vasculature seen in coeliac disease patients on a gluten-containing diet.     

The role of autoantibodies as diagnostic markers of autoimmune hepatitis

Autoantibody testing is the first step towards the diagnosis of autoimmune hepatitis, and it is essential in the evaluation of acute and chronic hepatitis of undetermined cause and allograft dysfunction following liver transplantation. A standard diagnostic repertoire has been promulgated, and other autoantibodies are emerging that may have prognostic value. Supplemental autoantibodies may prove useful in assessing patients who lack the standard markers or who are distinctive among those with conventional markers. Serologic testing will improve as assays are standardized by serum exchange workshops, core diagnostic batteries are codified and promulgated, and markers emerge that are tightly associated with pathogenic mechanisms, and closely reflect disease activity and outcome.     

Anti-Sm autoantibodies in systemic lupus erythematosus mice: a model system for disease-specific autoreactivity

Conclusions Our current understanding of the anti-Sm response is that it is SLE specific, antigen driven, and T cell dependent. It does not require a particular V_H-V_L Ig gene combination, but probably can be coded for by a limited number of such genes. It also appears in very high titers and in the isotypes which are characteristic of autoantibodies in autoimmune mice. Thus, the formation of anti-Sm antibodies in such mice probably reflects the basic immunoregulatory abnormalities that are fundamental to the spontaneous SLE syndrome in these animals.Future studies of anti-Sm antibodies should elucidate our understanding of the etiology of SLE. The basic questions that remain are: (1) what is the specificity of the helper T cells which are presumably required for the formation of anti-Sm antibodies in vivo? (2) what is the nature of the T-B collaboration that occurs? (3) what is the role of MHC class II? (4) why is the Sm antigen particularly targeted in this disease? (5) why is there some restriction of autoantibody gene usage for anti-Sm, antibodies? and (6) what are the cellular and genetic expressions of the fundamental immunoregulatory abnormalities that permit these animals to make anti-Sm antibodies?     

Expanding the targets available to therapeutic antibodies via novel disease-specific markers

The development of immunotherapies offers significant promise for clinical applications in cancer and infectious diseases. Here the authors describe a novel, integrated approach to immunotherapy that combines novel technologies to discover and target disease-specific peptide/HLA class I complexes. This unique class of markers makes the entire proteome accessible to antibody reagents and offers unsurpassed specificity for targeting cancerous and infected cells. Arm one of the three-armed approach uses an innovative technology for the efficient, direct discovery of new peptide/HLA class I markers. Arm two applies a powerful and inventive strategy to generate T-cell receptor mimics (TCRms), which are antibodies with exquisite binding specificity for peptide/HLA class I markers, and uses TCRms to validate the specific expression of markers on cancerous and infected cells. The third arm uses TCRms to target and kill diseased cells with high sensitivity and specificity. In summary, the combination of two pioneering technologies expands the repertoire of disease-specific markers that can be targeted by therapeutic antibodies and enables a powerful, integrated approach to HLA-based immunotherapy.     

Principles of use of surrogate markers and endpoints

Surrogate end-points are markers of biological mechanisms and require a mechanistic view on diseases. Thus, the validation of candidate surrogate end-points for the cardiovascular risk of sex steroids requires that a separate evaluation be made of the various clinical endpoints in which different biological mechanisms are likely to operate.

The case of venous thromboembolic (VTE) disease and arterial diseases is complex since they are multifactorial and multiple surrogate end-points are likely to be relevant. In addition sex steroids have many effects on biological mechanisms and the selection and validation of surrogates from the available bulk of changes in multiple mechanisms is a large enterprise. In addition, the combination of candidates in algorithms is required and at very early development stages only.

In practice, the validation of candidates requires the detection of changes or levels achieved in intervention trials with clinical end-points and such evaluations are scarce.

The observations of increased risk of VTE for first-time users of sex steroids indicate the occurrence of a susceptible subgroup, suggesting that effects in this group may be dissimilar to those in the population as a whole or quantitatively strongly different.     

Cytokeratin autoantibodies: useful serologic markers for toluene diisocyanate-induced asthma

To evaluate the clinical significance of autoantibodies to three major epithelial cytokeratins (CK)--CK8, CK18, and CK19--we compared 66 patients with toluene diisocyanate (TDI)-induced asthma (group I) with three control groups: 169 asymptomatic exposed subjects (group II), 64 patients with allergic asthma (group III), and 123 unexposed healthy subjects (group IV). Serum IgG, specific for human recombinant CKs, were measured by ELISA (enzyme linked immunosorbent assay), and ELISA inhibition tests were performed. The existence of these antibodies was confirmed by IgG immunoblot analysis. Anti-TDI-HSA (human serum albumin) IgE and IgG antibodies were measured by ELISA in the same set of the patients. The prevalence of CK8, CK18, and CK19 auotantibodies in group I was significantly higher than in the other three groups. Results of the ELISA inhibition test showed significant inhibition with the addition of three CKs in a dose-dependent manner. No significant association was found between CK autoantibodies and the prevalence of anti- TDI-HSA IgG and IgE antibodies. These results suggest that autoantibodies to CK18 and CK19 can be used as serologic markers for identifying patients with TDI-induced asthma among exposed workers.     

Antinuclear autoantibodies as potential antineoplastic agents

The immune system confines neoplasia at various stages of tumor development. Whereas the role of cellular immunity has been investigated widely and utilized in the clinic, the importance of humoral immunity in this process has begun to emerge only in recent years. Circulating antinuclear autoantibodies (ANAs) typically found in autoimmune conditions, have also been detected in cancer patients and in healthy elderly individuals. The pathogenic role of ANAs in autoimmunity is well studied; however, little research has been carried out to elucidate the functions of ANAs in cancer patients. Experimental data favoring the antitumor activity of ANAs might support the clinical testing of monoclonal ANAs as a cancer therapy, if confirmed by further experiments.     

Anti-annexins autoantibodies: their role as biomarkers of autoimmune diseases

Annexins are a group of 12 highly conserved proteins which exert several regulatory functions on cell biology. There are involved in numerous cell processes including vesicle trafficking, calcium signaling, cell growth, division, and apoptosis. Autoantibodies directed toward annexin I, II, V and XI have been reported, but their role and their clinical correlates are controversial. Annexin I exerts an anti-inflammatory effect by suppressing the generation of inflammatory mediators and anti-annexin I antibodies were detected in patients affected with rheumatoid arthritis, systemic (SLE) and cutaneous lupus erythematosus. Annexin II and V have a high affinity for phospholipids playing a pivotal role in the regulation of coagulation cascade. Anti-annexin II and anti-annexin V antibodies were found in patients with arterial or venous thrombosis, especially in those with autoimmune rheumatic diseases (ARD) such as SLE, primary antiphospholipid syndrome (APS) or systemic sclerosis. Anti-annexin V antibodies were also found in patients with pregnancy loss with or without APS. Annexin XI is involved in several biological pathways, particularly apoptosis and cell proliferation. Anti-annexin XI antibodies have been found in patients with SLE, undifferentiated connective tissue disease, rheumatoid arthritis, Sj?gren's syndrome and APS. The metanalysis of studies published up to now showed that the Odds Ratio for having an ARD in anti-annexin XI positive patients was 5.08 (95% CI 2.06-12.58).     

Tumour- associated autoantibodies as prognostic cancer biomarkers- a review

Throughout the process of carcinogenesis, autologous cells are transformed into cancer cells, leading to changes in their protein expression profiles. It has been suggested that mutations, protein misfolding, overexpression and aberrant post-translational modifications, changes in protein abundance or location can render tumour-associated antigens immunogenic. Subsequent changes in the tumour microenvironment may lead to humoral immune responses and therefore the production of tumour-associated autoantibodies. Hence, autoantibodies are suggested to be immunological biomarkers of aberrant cellular mechanisms occurring throughout tumourigenesis. Since autoantibodies represent a stable and amplified signature of the anti-tumour immune response that may be generated prior to the clinical detection of other tumour proteins and prior to the first clinically detectable signs of the cancer or its recurrence, there is great interest in using autoantibodies as diagnostic and prognostic blood-based biomarkers. In this review, we discuss the current evidence supporting the prognostic value of autoantibodies in a highly immunogenic cancer such as melanoma as well as breast, lung, colon, prostate and stomach cancer, the most commonly diagnosed cancers globally in 2020.     

General network of natural autoantibodies as immunological homunculus (Immunculus)

The term 'Immunculus' has been proposed for designation of the global system (network) of constitutively expressed natural autoantibodies (na-Ab) interacting specifically with different extracellular, membrane, cytoplasmic, and nuclear self-antigens. In healthy persons the repertoires of such na-Ab are surprisingly constant and characterized by minimal individual quantitative variations. On the other hand, abnormal metabolic deviations, which precede or accompany different diseases show easily detectable prominent changes, rather quantitative than qualitative, in the network of na-Ab in the patient's sera (Immunculus distortions). This phenomenon can be used for 'mapping' the state of physiological norm in terms of the millennia of na-Ab repertoires, and for the elaboration of methods for an early (pre-clinical) detection of potentially pathogenic metabolic changes. Can the individual features of the general network of constitutively expressed na-Ab reflect the functional state of the body and be used for 'mapping' of normal and pathological functional state? Can the changes in production of some biologically active na-Ab not only reflect the state of the body, but also be used for partial compensation of functional deficiency of certain molecular systems? These and related questions are discussed in this article. The research project 'Immunculus' is proposed for international cooperative investigations.     

Stress proteins as molecular markers of neurotoxicity

In response to many environmental and pathophysiologic stressful stimuli, cells undergo a stress response characterized by induction of a variety of proteins, including the heat shock protein family. The inducible heat shock protein 70 (hsp70) is believed to participate in an array of cellular activities, including cytoprotection. Normal brain cells have little detectable hsp70 RNA or protein. However, following a stressful condition hsp70 mRNA and protein are induced in different cell types depending on the severity and the nature of the stimulus. The induction of hsp70 protein correlates with the regional and cellular vulnerability to a particular injury as identified by standard histologic methods. The pattern of hsp70 expression differs in response to various neurotoxic stimuli, including hyperthermia, ischemia, seizures, hemorrhage, and N-methyl-D-aspartate receptor antagonist administration. Hsp70 expression is a useful marker of cellular injury and may help to identify previously unrecognized areas of vulnerability in the nervous system after a neurotoxic stimulus. Hsp70 may also play a neuroprotective role in the brain.     

Neurotrophic factors and autoantibodies to them as molecular predictors of cerebral dysfunctions

A complex of clinical and immunochemical studies was made in patients with chronic brain ischemia and ischemic stroke and in neonatal infants with CNS dysfunctions and retarded intrauterine development. Enzyme immunoassay was used to measure the levels of brain proteins with trophic properties--S100b, the major protein myelin, lectins CSL, R1, and the levels of primary and antiidiotypic antibodies to these proteins in the biological fluids of the patients. The findings suggest that the study brain proteins and autoimmune processes against these factors are involved in the mechanisms of the pathogenesis of the diseases in question and they enable changes and variations in the levels of neurotropic factors and their autoantibodies to be considered as predictors of brain ischemia and perinatal cerebral lesions.