anti-P Autoantibodies Research Articles

Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease.

The aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE). Mice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA. NSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.

Autoimmune anti-DNA and anti-phosphatidylserine antibodies predict development of severe COVID-19.

High levels of autoimmune antibodies are observed in COVID-19 patients but their specific contribution to disease severity and clinical manifestations remains poorly understood. We performed a retrospective study of 115 COVID-19 hospitalized patients with different degrees of severity to analyze the generation of autoimmune antibodies to common antigens: a lysate of erythrocytes, the lipid phosphatidylserine (PS) and DNA. High levels of IgG autoantibodies against erythrocyte lysates were observed in a large percentage (up to 36%) of patients. Anti-DNA and anti-PS antibodies determined upon hospital admission correlated strongly with later development of severe disease, showing a positive predictive value of 85.7% and 92.8%, respectively. Patients with positive values for at least one of the two autoantibodies accounted for 24% of total severe cases. Statistical analysis identified strong correlations between anti-DNA antibodies and markers of cell injury, coagulation, neutrophil levels and erythrocyte size. Anti-DNA and anti-PS autoantibodies may play an important role in the pathogenesis of COVID-19 and could be developed as predictive biomarkers for disease severity and specific clinical manifestations.

Atypical memory B-cells are associated with Plasmodium falciparum anemia through anti-phosphatidylserine antibodies.

Anemia is a common complication of malaria that is characterized by the loss of infected and uninfected erythrocytes. In mouse malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet+B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. In Plasmodium falciparum patients with anemia, we show that atypical memory FcRL5+T-bet+ B-cells are expanded and associate both with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia with other B-cell subsets and no association of other antibody specificities with FcRL5+T-bet+ B-cells is observed, revealing high specificity in this response. We also identify FcRL5+T-bet+ B-cells as producers of anti-PS antibodies in ex vivo cultures of naïve human peripheral blood mononuclear cells (PBMC) stimulated with P.-falciparum-infected erythrocyte lysates. These data define a crucial role for atypical memory B-cells and anti-PS autoantibodies in human malarial anemia.

Pathogenicity of lupus anti-ribosomal P antibodies: role of cross-reacting neuronal surface P antigen in glutamatergic transmission and plasticity in a mouse model.

To assess whether autoantibodies against ribosomal P (anti-P), which are possibly pathogenic in neuropsychiatric systemic lupus erythematosus (NPSLE), alter glutamatergic synaptic transmission and to what extent the cross-reacting neuronal surface P antigen (NSPA) is involved. We analyzed glutamatergic transmission and long-term potentiation (LTP) mediated by AMPA receptor (AMPAR) and N-methyl-d-aspartate receptor (NMDAR) by field excitatory postsynaptic potential (EPSP) at the CA3-CA1 synapse. AMPAR activation by patch-clamp recordings in primary ventral spinal cord neurons was analyzed. In primary hippocampal neurons, NSPA distribution was assessed by double immunofluorescence, and intracellular calcium changes were evaluated using Fura-2 AM. NSPA-LacZ reporter-knockin mice expressing a truncated NSPA were used to assess NSPA expression pattern and function in the brain using β-galactosidase staining and comparative electrophysiology, calcium responses, and water maze memory tests. NSPA was expressed in the brain in hippocampal CA1, dentate gyrus and ventral, but not dorsal, CA3 regions, encompassing postsynaptic regions and partial colocalization with NMDAR. Notably, NSPA-LacZ reporter-knockin mice showed impaired memory, and decreased NMDAR activity and LTP, with neurons insensitive to anti-P autoantibodies. Anti-P autoantibodies enhanced CA1 postsynaptic transmission, increasing AMPAR and NMDAR activity and leading to LTP abrogation after prolonged (20-minute) incubation. Our findings indicate that the neuronal cell surface target of anti-P, NSPA, is involved in glutamatergic synaptic transmission and plasticity related to memory in the hippocampus, and mediates the deleterious effects of anti-P on these processes. Cognitive impairment, as well as other diffuse NPSLE manifestations, may develop when anti-P autoantibodies have access to brain regions coexpressing NSPA, AMPAR, and NMDAR.

Human recombinant antibodies againstTrypanosoma cruziribosomal P2βprotein

Patients with chronic Chagas' Heart Disease (cChHD) develop an antibody response that is suspected to be involved in the cardiac pathogenesis. The response against Trypanosoma cruzi ribosomal P proteins is of particular interest, as these antibodies can cross-react with host cardiac receptors causing electrophysiological alterations. To better understand the humoral anti-P response we constructed a single-chain variable fragment library derived from a cChHD patient. The variable heavy and light regions were amplified from bone-marrow RNA and subcloned into the vector pComb3X. The phage library was subsequently panned against T. cruzi ribosomal P2β protein (TcP2β). We obtained 3 different human recombinant antibodies that specifically reacted with TcP2β in ELISA and Western blots. Two of them reacted with the C-terminal region of TcP2β, peptide R13, as the recombinant autoanti-P antibodies from Systemic Lupus Erythematosus (SLE) patients. Interestingly, the third one was specific for TcP2β but did not recognize R13, confirming the specific nature of the anti-P response in Chagas disease. Neither sequence nor VH usage similarities between Chagas and SLE anti-P autoantibodies were observed. Herein, the first human mAbs against TcP2β have been obtained and characterized showing that the humoral anti-P response is directed against the parasite and does not include an autoimmune component.

Clinical manifestation of systemic lupus erythematosus in patients with antiribosomal P protein antibodies

Antibodies against ribosomal P protein (anti-P) are detected predominantly in patients with systemic lupus erythematosus (SLE). However, the data on their frequency and clinical relevance remain inconclusive. The aim of the study was to assess the frequency as well as clinical and serological relevance of anti-P autoantibodies in Polish patients with SLE and to determine the significance of these antibodies in the diagnosis of SLE. Anti-P antibody levels were measured in the sera of 100 SLE patients using an enzyme-linked immunosorbent assay and Western blotting. All patients underwent a routine clinical and laboratory evaluation. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. Anti-P antibodies were detected in 14 of 100 patients. When compared to anti-P-negative patients, this group was characterized by earlier onset of SLE, higher disease activity, more frequent occurrence of fever and facial erythema, decreased serum levels of complement, and elevated levels of alanine and aspartate aminotransferases. In 2 cases, anti-P antibodies were the only serological marker of SLE detected in these patients. SLE with the presence of anti-P antibodies is characterized by an early onset and high disease activity.

Clinical and diagnostic value of ribosomal P autoantibodies in systemic lupus erythematosus

To analyse prospectively the diagnostic sensitivity and specificity as well as the clinical relevance of ribosomal P (anti-P) autoantibodies in a large cohort of SLE patients. The anti-P autoantibodies were evaluated in the serum of 200 Tunisian SLE patients at disease onset and 130 various control subjects by a sensitive immunodot assay. A complete laboratory evaluation and clinical examination were performed in each SLE patient. During the follow-up, the patients were regularly monitored for clinical parameters. Global SLE activity was measured by the ECLAM. The sensitivity and specificity of anti-P testing for SLE were 23.5 and 98.4%, respectively. The anti-P-positive samples 14/47 (29.8%), 27/47 (57.4%) and 5/47 (10.6%) were negative for anti-dsDNA, anti-Sm or both antibodies, respectively. The anti-P-positive patients showed more active disease activity and a much higher prevalence of arthritis. An association between IgG aCLs and anti-P antibodies was also found. However, anti-P antibodies were not associated with neuropsychiatric manifestations or lupus nephritis. This study does not seem to confirm the described association of anti-P antibodies with neuropsychiatric manifestations of SLE. However, it supports the anti-P antibody association with arthritis and disease activity as well as the presence of aCL. Based on our study and other related studies, we propose that, akin to anti-Sm and anti-dsDNA, anti-P antibodies detected by one agreed method may be considered for inclusion as a criterion for the classification of SLE.

Three-dimensional studies of pathogenic peptides from the c-terminal of Trypanosoma cruziribosomal P proteins and their interaction with a monoclonal antibody structural model

The acidic C-terminal peptides from Trypanosoma cruzi ribosomal P proteins are the major target of the antibody response in patients suffering Chagas chronic heart disease. It has been proposed that the disease is triggered by the cross-reaction of these antibodies with the second extra cellular loop of the β1-adrenoreceptor, brought about by the molecular mimicry between the acidic C-terminal peptides and the receptor's loop. To improve the understanding of the structural basis of the autoimmune response against heart receptors, the 3-dimensional structure of the C-terminal peptides of Trypanosoma cruzi ribosomal proteins P0 (EDDDDDFGMGALF) and P2β (EEEDDDMGFGLFD) were solved using the Electrostaticaly Driven MonteCarlo method. Their structures were compared with the second extra-cellular loop of our homology model of human rhodopsin and the existing experimental NMR structures of the C-terminal peptides from human P0 (EESDDDMGFGLFD) and from Leishmania braziliensis P0 (EEADDDMGFGLFD). Docking of Trypanosoma cruzi peptides P0, P2β and human rhodopsin loop into our anti-P2β monoclonal antibody homology model allowed to explore their interactions.The solution structure of peptides P0 and P2β can be briefly described as a bend. Although the global conformations of the peptides are not identical they shared a common region of four residues (3 to 6) that have a similar structure. The structural alignment of the five peptides also showed a surprising conformational similarity for the same residues. The antibody model and docking studies revealed a most remarkable feature in the active site, a positively charged, narrow and deep cavity where the acidic residues 3 to 6 were accommodated. These results suggest that the most important elements in the molecular peptide recognition by the antibody may be the shape of the loop and the presence of negative charges in positions 3–5 (P0, P2β) or a negative charge in position 4 (rhodopsin loop). This work describes clearly the interactions of the structural elements involved in the autoimmune mechanism of anti-P auto-antibodies cross-reaction and stimulation of the β1-adrenoreceptor and the visual pigment rhodopsin. Results from this study could lead eventually to the development of treatments to abolish receptor mediated symptoms in Chagas. PACS code: 87.15.-v

The β1 adrenergic effects of antibodies against the C-terminal end of the ribosomal P2β protein ofTrypanosoma cruziassociate with a specific pattern of epitope recognition

BALB/c mice immunized with recombinant Trypanosoma cruzi ribosomal P2beta protein (TcP2beta) develop a strong and specific antibody response against its 13 residue-long C-terminal epitope (peptide R13: EEEDDDMGFGLFD) that has a concomitant beta1-adrenergic stimulating activity. However, other animals that undergo similar immunizations seem tolerant to this epitope. To evaluate further the antibody response against the ribosomal P proteins, 25 BALB/c and 25 Swiss mice were immunized with TcP2beta. From the 50 animals, 31 developed a positive anti-R13 response, whereas 19 were non-responsive. From the 31 anti-R13 positive mice, 25 had anti-R13 antibodies that recognized the discontinuous motif ExDDxGF, and their presence correlated with the recording of supraventricular tachycardia. The other six had anti-R13 antibodies but with a normal electrocardiographic recording. These anti-R13 antibodies recognized the motif DDxGF shared by mammals and T. cruzi and proved to be a true anti-P autoantibody because they were similar to those elicited in Swiss, but not in BALB/c mice, by immunization with the C-terminal portion of the mouse ribosomal P protein. Our results show that the recognition of the glutamic acid in position 3 of peptide R13 defines the ability of anti-R13 antibodies to react with the motif AESDE of the second extracellular loop of the beta1-adrenergic receptor, setting the molecular basis for their pathogenic beta1 adrenoceptor stimulating activity.

Characterization of ribosomal P autoantibodies in relation to cell destruction and autoimmune disease.

Autoantibodies against the ribosomal P proteins are related to cell death and tissue destruction and are frequently exhibited in patients with systemic lupus erythematosus (SLE). In an attempt to explore the effect of tissue destruction on the induction of anti-P autoantibodies, we searched for anti-P autoantibodies by enzyme-linked immunosorbent assay in 201 antinuclear antibody (ANA)-positive individuals, in 10 patients with treated kidney SLE and in 45 acute leukaemia patients undergoing intensive chemotherapy. The autoantibody reactivity was further characterized using one- and two-dimensional immunoblot analysis and immunofluorescence. Anti-P were detected in 5.5% (11/201) of ANA-positive individuals, but not in kidney-affected SLE patients or in patients with leukaemia. Seven of 11 anti-P-positive patients had SLE (3/11), primary Sjögrens's syndrome (1/11) and other autoimmune diseases (3/11). A relation between disease activity and anti-P was suggested by follow-up examinations in one SLE patient, supported by the absence of anti-P autoantibodies in the 10 treated kidney SLE patients. Anti-P autoantibodies were detected by immunoblot in one patient with SLE indicating anti-P2 predominance and in the patient with Sjögrens's syndrome indicating anti-P1 predominance. Diverging humoral responses in these ANA- and anti-P-positive patients were further illustrated by immunofluorescence, elucidating varying nuclear reactivity and anti-P pattern. The observation of anti-P in individuals with active autoimmune disease, but not in patients with chemotherapy-induced cell damage, suggests that anti-P antibodies are part of a specific disease process, and not elicited as a response to cell destruction per se.

Sequence analysis, expression, and paratope characterization of a single-chain Fv fragment for the eukaryote ribosomal P proteins

The variable genes of monoclonal antibody (mAb) B10, specific for the C-terminal region of the eukaryotic ribosomal P protein, have been cloned as a single-chain Fv fragment (scFv) and expressed in Escherichia coli. The primary sequence of the variable regions of the B10 antibody, together with a detailed characterization of the reactive residues of the antigen, allowed the construction of a model of the paratope–epitope interaction, giving a first insight into the binding mechanisms of anti-P autoantibodies to their target peptides. The mAb and scFv could be useful for extensive P protein detection since both recognize the highly conserved motif DDxGF.

A murine monoclonal anti-idiotype to anti-ribosomal P antibodies: production, characterization, and use in systemic lupus erythematosus.

Overt anti-ribosomal P (anti-P) autoantibodies are restricted to a subset of systemic lupus erythematosus (SLE) patients, and are potentially pathogenic. Covert anti-P are detected in all other individuals. An idiotype (Id) network is nonoperational in those with overt anti-P, whereas it is functional in all others. The aim of this study was to produce a murine monoclonal (mAb) anti-Id to characterize the anti-P Id network in SLE. BALB/c mice were immunized with F(ab')(2) fragments of IgG anti-P from a patient with a broadly cross-reactive Id. One mAb was chosen (mAb41) that reacted preferentially to the immunogen. This IgG1 mAb bound comparably in ELISAs to affinity-purified anti-P from 11 SLE patients with overt anti-P. This binding was partially inhibited with ribosomal P antigen. In contrast, it did not bind to affinity-purified control autoantibodies, nor to normal human IgG. mAb41 inhibited anti-P binding to ribosomal P antigen in immunoassays and on Jurkat cells. No change was detected in patients' anti-P antibodies over time when mAb41 was used in Id-specific ELISAs. We conclude that mAb41 is an anti-Id that recognizes a public idiotope within the antigen-combining site of anti-P antibodies. Thus, it is analogous to its human counterparts, and potentially, would modulate the pathogenicity of anti-P autoantibodies in vivo.

Monoclonal antibodies against human ribosomal P proteins penetrate into living cells and cause apoptosis of Jurkat T cells in culture.

This study was designed to determine the role of autoantibodies to the ribosomal P protein (anti-P Abs) in the pathogenesis of systemic lupus erythematosus (SLE) using monoclonal anti-P antibodies (anti-P mAbs). Anti-P mAbs were prepared by a standard hybridoma procedure using recombinant human P1 and P2 proteins as immunogens. We studied the reactivities of these mAbs to P proteins, their binding and penetration capabilities in different cell lines and their apoptotic effects on Jurkat T cells. In addition to recognizing human P0, P1 and P2 proteins, the anti-P mAb 9B6-4 bound to 20-40% and penetrated 50-90% of astrocytes, Jurkat T cells and lung cancer cells via the P0 surface protein. Treatment with the mAb 9B6-4 also caused increases in the percentages of Jurkat T cells in the sub-G1 phase of the cell cycle (14.8%) and undergoing apoptosis (21.3%). Anti-P autoantibodies may play a role in the pathogenesis of lymphopenia or lymphocyte dysfunction in SLE.

Autoantibodies in systemic lupus erythematosus.

Cationic germ line gene-encoded anti-DNA antibodies appear to cause inflammatory lesions via deposition and in situ formation of immune complexes, but also perhaps through apoptosis of glomerular mesangial cells. Somatic mutation is not critical for the expression of the electrical net charge of anti-DNA. In one transgenic mouse model, the nephrogenicity of anti-DNA was dependent on the expression of interleukin alpha by epidermal cells. Anti-P autoantibodies are present in the serum of healthy children but are masked by IgG antibodies. Some anti-P antibodies appear to be a subset of antilymphocyte autoantibodies. It was confirmed that anti-Ro/SS-A antibodies react with structurally unrelated conformational epitopes. The combined results of immunofluorescence and enzyme-linked immunosorbent assay in the detection of antineutrophil cytoplasmic antibody has a 99.5% specificity for vasculitis among patients with connective tissue diseases. Antinucleosome antibodies are highly prevalent in patients with systemic lupus erythematosus and show an inverse correlation with nucleosome plasma levels. Transfected T-cell receptor alpha chains specific for nucleosomal autoepitopes from a Th clone that accelerates lupus nephritis, recognized the nucleosomal epitopes presented by antigen presenting cell-bearing 1-A molecules, as well as human DR molecules, via the classical major histocompatibility complex class II groove. IgG antibodies against (beta 2 -glycoprotein (GP)-1 are significantly associated with thrombosis in patients with antiphospholipid syndrome, with a specificity and sensitivity that ranges from 85% to 98% and 32% to 54%, respectively. The lupus anticoagulant activity, or the lack of it, of anti-beta 2-glycoprotein-1 appears to reside on the epitope specificity. Beta 2-glycoprotein-1 binds to apoptotic cells; in turn, anti-beta 2-glycoprotein-1 facilitate apoptotic cell clearance by macrophages. The recently described anti-A2/RA33 autoantibody appears to recognize an epitope capable of distinguishing patients with lupus or with rheumatoid arthritis from those with mixed connective tissue disease.

The presence of masked antiribosomal P autoantibodies in healthy children

To determine if antiribosomal P (anti-P) autoantibodies are present in healthy children. Sera from healthy children were screened for anti-P by conventional enzyme-linked immunosorbent assay and immunoblot techniques. Sera were also treated with immobilized ribosomal P antigens on nitrocellulose strips; affinity-purified fractions were tested for anti-P by high-sensitivity immunoblot. The relative binding affinities were compared for affinity-purified anti-P antibodies from healthy children and adults, and patients with systemic lupus erythematosus. IgG fractions of anti-P-depleted sera from healthy children were assessed for inhibition of autologous anti-P activity. Conventional serologic screening showed no IgG nor IgM anti-P in 88 untreated sera. IgG anti-P were unmasked in all 79 sera treated by the membrane batch affinity technique. IgM anti-P were identified in 27 of the treated sera; the percentage of positive sera decreased with increasing age (chi(2) for linear trend P = 0.00081). Affinity-purified anti-P from children had relative binding affinities similar to those of anti-P from other groups. Sera from healthy children contained inhibitory IgG antibodies to anti-P. These results show that anti-P autoantibodies are present in all healthy children. The majority of these autoantibodies are masked by IgG antibodies, suggesting concordant development of a regulatory network.

The presence of masked antiribosomal P autoantibodies in healthy children

Objective To determine if antiribosomal P (anti-P) autoantibodies are present in healthy children. Methods Sera from healthy children were screened for anti-P by conventional enzyme-linked immunosorbent assay and immunoblot techniques. Sera were also treated with immobilized ribosomal P antigens on nitrocellulose strips; affinity-purified fractions were tested for anti-P by high-sensitivity immunoblot. The relative binding affinities were compared for affinity-purified anti-P antibodies from healthy children and adults, and patients with systemic lupus erythematosus. IgG fractions of anti-P-depleted sera from healthy children were assessed for inhibition of autologous anti-P activity. Results Conventional serologic screening showed no IgG nor IgM anti-P in 88 untreated sera. IgG anti-P were unmasked in all 79 sera treated by the membrane batch affinity technique. IgM anti-P were identified in 27 of the treated sera; the percentage of positive sera decreased with increasing age (χ2 for linear trend P = 0.00081). Affinity-purified anti-P from children had relative binding affinities similar to those of anti-P from other groups. Sera from healthy children contained inhibitory IgG antibodies to anti-P. Conclusion These results show that anti-P autoantibodies are present in all healthy children. The majority of these autoantibodies are masked by IgG antibodies, suggesting concordant development of a regulatory network.

Antibodies to ribosomal P proteins of Trypanosoma cruzi in Chagas disease possess functional autoreactivity with heart tissue and differ from anti-P autoantibodies in lupus.

Anti-P antibodies present in sera from patients with chronic Chagas heart disease (cChHD) recognize peptide R13, EEEDDDMGFGLFD, which encompasses the C-terminal region of the Trypanosoma cruzi ribosomal P1 and P2 proteins. This peptide shares homology with the C-terminal region (peptide H13 EESDDDMGFGLFD) of the human ribosomal P proteins, which is in turn the target of anti-P autoantibodies in systemic lupus erythematosus (SLE), and with the acidic epitope, AESDE, of the second extracellular loop of the beta1-adrenergic receptor. Anti-P antibodies from chagasic patients showed a marked preference for recombinant parasite ribosomal P proteins and peptides, whereas anti-P autoantibodies from SLE reacted with human and parasite ribosomal P proteins and peptides to the same extent. A semi-quantitative estimation of the binding of cChHD anti-P antibodies to R13 and H13 using biosensor technology indicated that the average affinity constant was about 5 times higher for R13 than for H13. Competitive enzyme immunoassays demonstrated that cChHD anti-P antibodies bind to the acidic portions of peptide H13, as well as to peptide H26R, encompassing the second extracellular loop of the beta1 adrenoreceptor. Anti-P antibodies isolated from cChHD patients exert a positive chronotropic effect in vitro on cardiomyocytes from neonatal rats, which resembles closely that of anti-beta1 receptor antibodies isolated from the same patient. In contrast, SLE anti-P autoantibodies have no functional effect. Our results suggest that the adrenergic-stimulating activity of anti-P antibodies may be implicated in the induction of functional myocardial impairments observed in cChHD.

Anti-P antibodies and neuropsychiatric lupus erythematosus.

A high proportion of patients with SLE develop neuropsychiatric lupus during the course of their disease. The expression of disease varies significantly in terms of clinical manifestations, onset, and severity, so that this form of lupus remains a major diagnostic and therapeutic challenge. Because affected tissue cannot be sampled and animal models are not readily available, scientific investigation is considerably hampered. Approximately 15% of lupus patients have anti-P antibodies. These autoantibodies are highly specific for SLE. Most series show a highly significant association between anti-P and lupus psychosis, and this result is now confirmed in a series of 336 SLE patients. The mechanism explaining this association is uncertain and may simply reflect an immune response to damaged tissue. However, the possibility that the antibodies are pathogenic by directly binding to cell-surface receptors on neuronal cells or that they penetrate cells and inhibit protein synthesis within the cell requires further investigation. Whether T cells are involved in the pathogenesis of CNS disease is an important question that has received little attention. As in the CNS of patients with multiple sclerosis and patients with other autoimmune diseases, excess production of cytokines may contribute significantly to organ inflammation. We report associations between anti-P autoantibodies and certain MHC class II alleles, particularly HLA-DQB1*0602. These findings support a role for T cells in anti-P autoantibody production and encourage further studies of the role of autoantigen-specific T and B cells in injury to the central nervous system.

Autoimmunity and cancer - Beneficial relationships

Autoimmune diseases are the consequence of the immune system attack on the self. Autoimmunity, sometimes, is reflected through the production of autoantibodies to various self antigens leading to cellular malfunction or destruction. In the current study we employ such autoantibodies for the treatment of cancer originated from the respective normal cells. This concept is wide and entails many autoimmune disorders and diversity of malignant conditions. To illustrate the therapeutic and practical potential we depicted four examples: vitiligo and melanoma - vitiligo is considered dermatologic autoimmune disorder presented as depigmented skin areas. The destruction of the pigmented cells (melanocytes) is mediated by autoantibodies. We have purified these anti-melanocyte antibodies from patients with vitiligo and showed their cytotoxic effect towards malignant melanoma cells in vitro and in vivo; anti-phospholipid syndrome (APLS) and cancer-cancer cells differ from normal cells by the expression of phosphatydilserine (PS) on their outer membrane surface. We have used such anti-PS autoantibodies, derived from patients with APLS, as effective treatment for melanoma in a murine system; Autoimmune hemolytic anemia (AIHA) and hematological malignancies - in patients with AIHA, the red blood cells (RBC) destruction is mediated by binding of autoantibodies to RBC. We have shown the specific binding of these anti-RBC autoantibodies to RBC and to malignant cells of the erythroid lineage. Thus, these autoantibodies may have diagnostic/therapeutic potential for conditions such as erythroleukemia and polycythemia vera; anti-lymphocyte antibodies and lymphoproliferative diseases - in SLE and other systemic autoimmune conditions autoantibodies directed against lymphocytes can be found. These cytotoxic antibodies can be targeted against lymphocytes of lymphoproliferative diseases such as chronic lymphocytic leukemia, or lymphoma. The diversity of autoimmune diseases provides a great source for human preformed highly specific autoantibodies which can be used as an effective immunotherapy by themselves, for diagnostic purposes, as a cell specific carrier conjugated to other cytotoxic agents and in combined therapy in the combat against cancer.

Acquired Protein S Deficiency, Likely due to Anti-PS Autoantibodies, following a Thrombotic Event in a Patient with a Systemic Lupus erythematosus

Acquired Protein S Deficiency, Likely due to Anti-PS Autoantibodies, following a Thrombotic Event in a Patient with a Systemic Lupus erythematosus