Autism spectrum disorders are associated with an elevated autoantibody response to tissue transglutaminase-2.

We report that a significant number of autistic children have serum levels of IgA antibodies above normal to the enzyme tissue transglutaminase II (TG2), and that expression of these antibodies to TG2 is linked to the (HLA)-DR3, DQ2 and DR7, DQ2 haplotypes. TG2 is expressed in the brain, where it has been shown to be important in cell adhesion and synaptic stabilization. Thus, these children appear to constitute a subpopulation of autistic children who fall within the autism disease spectrum, and for whom autoimmunity may represent a significant etiological component of their autism.

Laboratory findings in psoriatic arthritis.

Psoriatic arthritis (PsA) has been classically defined as an inflammatory arthritis associated with psoriasis. However, in comparison with other relevant inflammatory arthropathies, in which a definite diagnosis is frequently possible only by means of laboratory investigations, in PsA true laboratory diagnostic markers are lacking. Some markers are utilised more to differentiate other diseases than to characterise PsA. For example in polyarticular PsA, which may be in some cases indistinguishable from RA, the rheumatoid factor (RF) or the more specific and recently introduced antibodies to cyclic citrullinated peptides (anti-CCP), may be useful to better identify RA. However, RF was found in 5% to 13% of patients with PsA, and anti-CCP may be observed in almost similar percentage. The determination of ESR and/or CRP is frequently disappointing in PsA, since they are both elevated in only half of the patients with PsA. However, ESR and/or CRP are included in the most utilised response criteria for RA, such as ACR and DAS, and, in addition are also considered reliable in the assessment of PsA. Furthermore, elevated levels of ESR have been proposed as one of the best predictors of damage progression and, in addition, a low ESR seems protective, while an ESR >15 mm/h is one of the factors associated with an increased mortality in PsA. The synovial fluid (SF) effusion is much higher in PsA, in comparison with other arthropathies. When available, SF analysis may offer additive information useful for the diagnosis, such as the increased number of leukocytes, which underlines the inflammatory nature of the effusion even in a patient with normal serum levels of acute phase response. We found that elevated IL-1 levels in SF of patients with early disease (<6 months), may be predictive of an evolution in polyarticular form at follow-up. This observation is in keeping with the crucial role that inflammatory cytokines play in PsA, probably related to a genetic predisposition. The recent introduction in PsA of anti-TNF-alpha agents and the demonstration of their efficacy in the management of many clinical disease expressions including peripheral arthropathy, axial involvement, enthesopathy and skin manifestations, have stimulated the research also in the field of the possible laboratory markers.

Two-year follow-up of anti-transglutaminase autoantibodies among celiac children on gluten-free diet: comparison of IgG and IgA.

OBJECTIVES: To investigate the evolution of IgA and IgG autoantibodies against tissue transglutaminase (tTGase) in celiac patients on gluten-free diet (GFD). METHODS: IgA and IgG anti-tTGAse autoantibodies was evaluated in 93 patients (58 girls and 35 boys; mean age 3.56 +/- 3.04 years; range 0.94-17.5 years) at diagnosis of celiac disease and after 1, 2, 4, 6, 12, 18, 24 months of follow-up on GFD. Autoantibodies were measured with a radioassay using in vitro transcribed-translated human recombinant tTGAse, and immune complexes were precipitated with protein A- or anti-IgA-agarose for IgG and IgA, respectively. RESULTS: Autoantibody titers started to decline very soon after removal of gluten, and no significant differences in the decrease rate between IgG and IgA antibodies were observed. After 6 months on GFD, 63 and 49% of the patients were negative for IgG and IgA, respectively. Patients who remained autoantibody-positive after 6 months of treatment initially presented with significantly higher titers at the time of diagnosis compared to patients that had lost their antibodies by that time. Children diagnosed before the age of two years presented lower autoantibody titers, while patients positive for HLA-DR7 had higher anti-tTGase levels, especially IgA. CONCLUSIONS: There are no differences in the performance of IgG and IgA class autoantibodies in the evolution of celiac patients. Between 3 and 6 months on GFD, almost half of the patients are negative for anti-tTGase antibodies. In our experience, they can be of help in evaluating compliance with diet, at least during the first two years of treatment.

Long-term detection of microchimaerism in peripheral blood after pretransplantation blood transfusion.

Renal allograft survival is prolonged after pretransplantation blood transfusion. The aim of this study was to test retrospectively the development and persistence of microchimaerism after pretransplantation blood transfusion and to assess whether the type of blood transfusion (partially matched [= sharing of at least one HLA-B and one HLA-DR antigen between blood donor and recipient] versus mismatched) influences the (continued) presence of donor-type cells. A sensitive nested PCR technique based on HLA-DRB1 allele-specific amplification using sequence-specific primers (detection level: one donor cell among 10(5) recipient cells) for detection of donor cells was implemented in our laboratory. We studied 21 patients for microchimaerism in the peripheral blood compartment, following blood transfusion. Our preliminary data show that microchimaerism was detectable up to 8 weeks after blood transfusion. In all patients receiving a partially matched blood transfusion, donor-type cells were detected in the first week after transfusion, in 7/8 patients 2-4 weeks after transfusion, and in some patients up to 8 weeks after transfusion. After mismatched transfusion a tendency to shorter duration of microchimaerism was observed.

HLA-DR7 predicts the response to alkylating agents in steroid-sensitive nephrotic syndrome.

There is a lack of reliable predictors of the response to alkylating agents in children with idiopathic nephrotic syndrome (NS). HLA-DR7 is strongly associated with the frequency of relapses in steroid-sensitive NS before cytostatic therapy. We therefore examined retrospectively the time to the first relapse and the incidence of subsequent relapses in 54 HLA-typed children with frequently relapsing NS, after treatment with cyclophosphamide (n = 49) or chlorambucil (n = 5) for 8 or 12 weeks; 38 patients were HLA-DR7 positive and 16 negative with 80% in both groups being steroid dependent. HLA typing was performed using serological or DNA typing methods. Renal biopsy showed minimal glomerular changes. A lower proportion of HLA-DR7 positive than negative patients remained in remission after 3 years (36% vs. 81%, P < 0.02) and 5 years (36% vs. 72%, P < 0.03). In the first 3 years after cytostatic therapy the mean number of prednisone-treated relapses was 1.3/patient per year in HLA-DR7-positive patients compared with 0.4 in negative patients (P < 0.025). There was no statistically significant difference in the proportion of relapse-free patients with and without steroid dependency. The HLA status predicts the response of NS patients to alkylating agents better than the rate of previous relapses.

HLA-DR7 in association with chlorpromazine-induced lupus anticoagulant (LA).

The presence of anti-phospholipid antibodies (aPL) has been associated with the major histocompatibility complex (MHC) genes. These autoantibodies occur in individuals with infections such as that produced by the human immunodeficiency virus 1 (HIV-1) or with syphilis, but they can also occur in drug-induced lupus-like syndromes. In the present study, we analysed the presence of aPL (detected as lupus anti-coagulant) and its relationship with the MHC markers in 93 Caucasian psychiatric patients chronically treated with chlorpromazine. Forty-one out of 93 patients were positive for LA, and the HLA-DR7 antigen was significantly increased in LA-positive patients as compared to normal controls or LA-negative patients (PC = 0.024, RR = 2.12 and P = 0.05, RR = 1.57, respectively). Likewise, we noted a significantly increased frequency of HLA-B44 in LA-positive patients as compared to normal controls (PC = 0.024, RR = 2.12), but not when compared to aPL-negative patients. No significant differences were found among any other class I, II or III MHC antigens. Haplotype analysis showed that DR7 was mostly part of the HLA-B44-DR7-FC31 and B7-DR7-SC31 haplotypes. These results suggest that the HLA-DR7 antigen might be playing a role in the production of aPL in chlorpromazine-treated patients.

Persistent polyclonal lymphocytosis with binucleated B lymphocytes: a genetic predisposition.

Persistent lymphocytosis is usually associated with a malignant lymphoproliferative disease (MLPD). We report six female patients presenting a chronic, moderate lymphocytosis of 2-16 years duration with atypical binucleated lymphocytes on peripheral blood smears. Further investigation showed a polyclonal increase in serum IgM and HLA-DR7 phenotype in all patients. The B cells were polyclonal because Southern hybridization of DNA and polymerase chain reaction failed to demonstrate a clonal rearrangement of immunoglobulin heavy chain genes. Peripheral blood examination showed binucleated lymphocytes in a family member of two of the cases; taken together with the association with HLA-DR7 these data suggest a genetic predisposition. The identification of this benign syndrome is important in order to prevent its misdiagnosis as a MLPD.