High prevalence of antineuronal antibodies in Tunisian psychiatric inpatients.

The authors aimed to determine the prevalence of antineuronal antibodies in 103 psychiatric inpatients and 41 control subjects with no history of malignancies or neurological disorders. All sera were tested by indirect immunofluorescence and positive sera by immunoblot. Using immunofluorescence, antineuronal nuclear autoantibodies were detected in 20 patients and none of the control subjects, and antibodies reacted with the cytoplasm of Purkinje cells in six patients and two control subjects. The immunoblot confirmed well-characterized antineuronal antibodies only in five patients: two had anti-Ri and three had anti-Yo antibodies. After a follow-up of 5 years, none of these patients developed neurological disorder or malignancy.

WNT signaling and chondrocytes: from cell fate determination to osteoarthritis physiopathology.

CONTEXT: Osteoarthritis (OA) is an articular disorder leading to the degradation of articular cartilage phenotypical chondrocytes modifications, including the acquisition of a fibroblast-like morphology, decreased expression of collagen type II, and increased expression of fetal collagen type I, metalloproteinase 13 and nitric oxide synthase. This promotes matrix degradation and unsuccessful cartilage repair. WNT signaling constitutes one of the most critical biological processes during cell fate assignment and homeostasis. OBJECTIVES: This review aims to give an insight on results from the studies that were interested in the involvement of WNT in OA. METHODS: Studies were selected through a pubmed search. RESULTS: Recent genetic data showed that aberration in WNT signaling may be involved in OA. WNT signals are transduced through at least three cascades: the canonical WNT/ß-catenin pathway, the WNT/Ca(2+) pathway and the WNT/planar cell polarity pathway. Most of the studies used in-vitro models to elucidate the involvement of WNT in the physiopathology of OA. These studies analyzed the expression pattern of WNT pathway components during OA such as WNT5, WNT7, co-receptor LRP, ß-catenin, WNT target genes (c-jun, cyclins) and/or the interaction of these components with the secretion of OA most important markers such as IL-1, collagens, MMPs. Results from these studies are in favor of a deep involvement of the WNT signaling in the physiopathology of OA either by having a protective or a destructive role. CONCLUSION: Deeper researches may eventually allow scientists to target WNT pathway in order to help develop efficient therapeutic approaches to treat OA.

Notch signaling is involved in human articular chondrocytes de-differentiation during osteoarthritis.

CONTEXT: During osteoarthritis (OA), chondrocytes undergo de-differentiation, resulting in the acquisition of a fibroblast-like morphology, decreased expression of collagen type II (colII) and aggrecan, and increased expression of collagen type I (colI), metalloproteinase 13 (MMP13) and nitric oxide synthase (eNOS). Notch signaling plays a crucial role during embryogenesis. Several studies showed that Notch is expressed in adulthood. OBJECTIVE: The aim of our study was to confirm the involvement of Notch signaling in human OA at in vitro and ex vivo levels. MATERIALS AND METHODS: Normal human articular chondrocytes were cultured during four passages either treated or not with a Notch inhibitor: DAPT. Human OA cartilage was cultured with DAPT for five days. Chondrocytes secreted markers and some Notch pathway components were analyzed using Western blotting and qPCR. RESULTS: Passaging chondrocytes induced a decrease in the cartilage markers: colII and aggrecan. DAPT-treated chondrocytes and OA cartilage showed a significant increase in healthy cartilage markers. De-differentiation markers, colI, MMP13 and eNOS, were significantly reduced in DAPT-treated chondrocytes and OA cartilage. Notch1 expression was proportional to colI, MMP13 and eNOS expression and inversely proportional to colII and aggrecan expression in nontreated cultured chondrocytes. Notch ligand: Jagged1 increased in chondrocytes culture. DAPT treatment resulted in reduced Jagged1 expression. Notch target gene HES1 increased during chondrocyte culture and was reduced when treated with DAPT. CONCLUSION: Targeting Notch signaling during OA might lead to the restitution of the typical chondrocyte phenotype and even to chondrocyte redifferentiation during the pathology.

Celiac disease in Tunisian children: a second screening study using a "new generation" rapid test.

This work aims to estimate celiac disease prevalence in school-children in the island of Djerba and assess rapid method feasibility for screening. We screened 2064 schoolchildren by a rapid method to detect IgA anti-tissue transglutaminase and IgA deficiency. Children with positive results were tested for IgA anti-transglutaminase and anti-endomysium by conventional tests. In positive children, intestinal biopsy was performed. IgA deficiency suspected by rapid method was confirmed by nephelometry. In these cases IgG anti-endomysium was performed. Rapid test was positive in 7 children; conventional serology was positive in all and 6 of them accepted the biopsy. Total villous atrophy was observed in 5 while intestinal mucosa was normal in one. Among children with positive serology, 3 had silent form, 1 chronic diarrhea, one growth failure and 2 had borderline growth. IgA deficiency was suspected in 13 cases and was confirmed in 11 children tested. Prevalence of celiac disease was 0.24-0.34% and that of IgA deficiency 0.5-0.6%. This screening study confirms that celiac disease is relatively common in schoolchildren in Tunisia. It confirms also that even those with symptoms typical for celiac disease escape diagnosis. Rapid test is better accepted by parents and children than test requiring a venous blood sample.

Anomalies of intra-synovial citrullination: is there any interest in the diagnosis of early rheumatoid arthritis?

Autoantibodies to citrullinated proteins (ACPA) are specifically associated with rheumatoid arthritis (RA) and seem to play an important role in its pathogenesis. The specific immunological conflict between ACPA and citrullinated fibrin plays a major role in the self-maintenance of synovial inflammation by forming fibrin deposits in the synovial tissue. These deposits, secondarily citrullinated by a local peptidylarginine deiminase (PADI) enzyme activity, seem to maintain the immunological conflict and the inflammation. Our objective in this work is to study the anomalies of citrullination in a group of patients with early RA, in comparison with a control group of patients suffering from undetermined inflammatory arthritis, osteoarthritis and spondyloarthropathy. For this purpose, we used an enzyme-linked immunosorbent assay (ELISA) to determine the levels of ACPA in serum and synovial fluid. By immunohistochemistry, subtype 4 of PADI was also sought in the synovial biopsies taken from all our patients. We found that the ACPA levels in serum and synovial fluid were significantly higher in patients with RA. The enzyme PADI4 was found only in the group with RA and was statistically correlated with ACPA mean levels in sera and synovial fluid. The expression of PADI4 seems to correlate with intra-synovial deposits of fibrin in RA. However, determination of synovial ACPA levels and detection of intra-synovial PADI4 deposits are of no additional benefit compared with assessment of ACPA levels in serum for the diagnosis of early RA.

Spectrum of autoantibodies in Tunisian psychiatric inpatients.

One hundred and three psychiatric inpatients (74 men) were assessed for a wide spectrum of autoantibodies including antinuclear, antismooth muscle, antimitochondrial, antiDNA, anti-phospholipid, anti-cardiolipin IgG and IgM, antikeratin, rheumatoid factor, antithyroperoxydase, antigliadin IgA and IgG, antitransgutaminase, and antiendomysium antibodies. Four groups of patients were considered separately, including 47 with schizophrenia, 23 with schizoaffective disorder, 16 with bipolar disorder and 17 patients with other different psychiatric diagnosis. Forty one healthy, age- and sex-matched blood donors were used as a control group. There were no significant difference in the prevalence of the different autoantibodies between patients (N = 103) and controls except for antigliadin IgG (30.1 vs 9.8 respectively, p = 0.01). Presence of autoantibodies was influenced by age but not by sex or treatment. As for diagnosis categories, patients with bipolar disorder presented significantly more autoantibodies than the three other categories and controls. These results point out a possible autoimmune activation in at least a subgroup of psychiatric patients especially amongst those suffering from bipolar disorder.

Is the rapid whole blood test useful for diagnosis and monitoring celiac disease in children?

AIM: To evaluate a new whole blood rapid test for the detection of IgA anti-transglutaminase (ATG) for diagnosis and diet survey of celiac disease (CD). METHODS: 57 children, 20 of them were CD patients on a gluten-free diet and 37 were under suspicion of CD were enrolled. IgAATG was detected by the conventional ELISA test and the new rapid whole blood test. RESULTS: Concordance between the 2 tests was 96.4%. All patients positive with ELISA were also positive by the rapid test. Only 2 patients were slightly positive by the rapid test and negative by ELISA. CONCLUSION: Whole blood rapid test seems to be as performant as ELISA test for IgAATG detection.

HLA-B, DR and DQ antigens polymorphism in Tunisian patients with ankylosing spondylitis (a case-control study).

The objective of the study is to assess the distribution of HLA-B genes, HLA-B27 subtypes, HLA-DRB1 and HLA-DQB1 alleles in patients with ankylosing spondylitis (AS) and in control subjects in the Tunisian population and to compare their distribution with that found in other countries. This is a case-control study that included 100 consecutive patients (85 males/15 females) with AS according to the modified New York criteria and 100 control individuals. HLA-B, B27 subtypes and class II (DR and DQ) typing of all subjects was performed by polymerase chain reaction amplification with sequence-specific primers (PCR-SSP). HLA-B27 was found in 62% of patients against 3% in controls (P = 0.0000, OR = 52.6, 15.6 < CI < 166.7). On the other hand, B*07 and B*51 were significantly decreased in comparison with controls (P = 0.01, OR = 0.3, 0.1 < CI < 0.8 and P = 0.0000, OR = 0.2, 0.1 < CI < 0.4, respectively). Eight B*27 subtypes were identified in the AS group, but the most frequent ones were B*2702 (32%) and B*2705 (24%). Among HLA-DRB1 alleles, a significant increase in DRB1*11 was found in comparison with controls (P = 0.01, OR = 2.2, 1.2 < CI < 4.5). However, DRB1*13 had a negative association with AS (P = 0.01, OR = 0.4, 0.2 < CI < 0.8). For HLA-DQB1 alleles, a significant positive association with DQB1*03 was observed in AS group (P = 0.03, OR = 1.8, 1.0 < CI < 3.4). Multivariate analysis by logistic regression revealed that DRB1*11 and DQB1*03 had no direct links with the disease, but were dependent on the presence of HLA-B27. Moreover, B*07 and B*51 seemed to have independently a negative correlation with AS, but DRB1*13 seemed to depend on B*51. Haplotypes carrying B27 were significantly associated with AS and those carrying B*07 or B*51 were negatively correlated with the disease. In conclusion, our study confirms that B27 predisposes to AS while B*07 and B*51 are negatively correlated with the disease.

[Hereditary complement C5 deficiency: study of 3 Tunisian adult cases and literature review]. / Deficit héréditaire en protéine C5 du complément: etude de 3 cas tunisiens de l'adulte et revue de la littérature.

BACKGROUND: The complement system is one of the main effectors of both innate and adaptive immunity. Hereditary complement deficiency, mainly those of the terminal pathway (C5-C9), is at increased risk for septic meningitides particularly meningococcal ones. AIM: to assess clinical and biochemical features of 3 Tunisian adults with C5 hereditary complement deficiency (C5D), with a familial study performed for two of them. METHODS: Functional activity of the classical and the alternative pathway of complement (CH50 and AP50 respectively) were measured according to standards haemolytic procedures. Serum concentration of complement components were determined by nephelemetry and ELISA. C5D was diagnosed when CH50, AP50 and C5 antigenic level were highly decreased. RESULTS: Our patients were 2 men and one woman. All these patients presented clinical symptoms of septic meningitides. Meningococcal orign was confirmed in one case. C5 level varies between 0 and 0.4%. Levels of other complement components: Clq, C3, C4, properdine, C6, C8 and C9 were normal. Antigenic C7 level was 50% in the female patient. Familial study revealed no similar hereditary complement deficiency in relatives. CONCLUSION: Only 27 cases with C5D were reported in the literature. The description of 3 cases in our series demonstrates that: * C5D is not rare in Tunisia, ** C5D is clinically commonly complicated by meningitides with unconstant severity, *** C5D is biologically caracterised by a variable level of the plasmatic C5 component.

Spectrum of autoantibodies in Tunisian adult type 1 diabetes mellitus.

As an autoimmune disease, type 1 diabetes mellitus (T1DM) is characterized by the presence of several autoantibodies. The aim of this study was to examine a broad spectrum of antibodies in Tunisian adult T1DM and to compare their prevalence with a healthy control group. Two hundred sixty-one diabetics and 100 healthy blood donors were enrolled in this study. Indirect immunofluorescence was performed for the detection of islet cell, antiendomysial, antinuclear, antimitochondrial, antismooth muscle, antireticulin, and antikeratin antibodies. Enzyme-linked immunosorbent assay was used for measuring anticardiolipin, antigliadin, antitransglutaminase, and antithyroperoxidase antibodies. Latex agglutination was used for the detection of rheumatoid factors. As expected, islet cell antibodies were the most frequent (33.7%). Antigliadin, antithyroperoxidase, and antikeratin antibodies were relatively frequent (18%, 15.3%, and 10.3%, respectively) and were statistically more prevalent in diabetics than in controls. There was no correlation between diabetes duration and any autoantibody, except for islet cell antibodies that were more frequent at the onset of diabetes. Several autoantibodies nonspecific of diabetes are frequent in diabetic patients, which may be associated with or predictors of some autoimmune diseases, and can also reflect a special profile of autoimmunity in diabetics in comparison to healthy controls.

Hereditary complement deficiency and lupus: report of four Tunisian cases.

The aim of the study was to assess the clinical and immunological profile of lupus erythematosus (LE) patients with inherited complement deficiency (ICD). A laboratory-based study was conducted in which all LE patients with hypocomplementemia were included. ICD was assessed by hemolytic and antigenic assays. Type I C2 deficiency was assessed by polymerase chain reaction (PCR). ICD was diagnosed in four cases. In three systemic LE patients, ICD were: homozygous C2 deficiency in the first case, heterozygous C2 deficiency in the second, and homozygous C1q deficiency in the third case. In a discoid LE patient, a combined homozygous C2 and C6 deficiency was diagnosed. Almost all of our patients presented the classical clinical and immunological features of LE associated with ICD. Severe lupus with renal involvement and recurrent infections was present in half of the patients suggesting that these patients are prone to a serious management.

Pediatric systemic lupus erythematosus with C1q deficiency.

Hereditary deficiency of each component of the classical pathway is associated with increased susceptibility to lupus erythematosus (LE). Both the severity of the disease and the strength of this association are greatest for homozygous C1q deficiency, which is extremely rare. In fact, more than 90% of all individuals with deficiency of this component have LE. We report a 3-year-old female infant with history of discoid LE treated with topical corticosteroids for 1 year. She was referred to pediatric department for an exacerbation and extension of cutaneous lesions toward front-arm, hands, legs and feet, a glomerulonephritis, and thrombopenia. Immunologic tests revealed a positive speckled antinuclear antibody at 1/1600 with positive anti-Sm, anti-SSA, and anti-RNP antibodies. Test for anti-DNA was negative. These findings were compatible with a transition to a systemic form of lupus. Systemic corticosteroid treatment was started; however, the patient died by a severe digestive hemorrhage. Hemolytic complement activity (CH50) was undetectable in serum despite normal levels of C3 and C4 suggesting a deficiency of an early component of the complement cascade. Measurement of hemolytic assay for C1 functional activity was less than 1%. C1q deficiency was confirmed by a double immunodiffusion and ELISA using sheep polyclonal anti-C1q antibodies. C1q deficiency is a rare genetic disorder. Thirty-eight of the 41 patients reported to date have developed systemic LE. C1q deficiency may cause systemic LE via a critical role of this component in the physiological clearance of apoptotic cells.

Immunogenetics of pemphigus: an update.

Pemphigus are rare but informative models of organ-specific autoimmune diseases, resulting from the interplay of environmental, genetic and stochastic factors. There are many arguments to consider that pemphigus have a genetic basis involving, as many other autoimmune diseases, several different genes with additive or synergistic effects. So far, the unique strategy used to identify the contributive loci has been direct analysis of candidate genes through conventional case-control association studies. The major histocompatibility complex in particular the class II locus was demonstrated to be associated with pemphigus with a high rate of replicability. The progresses in the understanding of pemphigus physiopathology and the development of new molecular tools offer new perspectives to unveiled the genetic basis of this group of autoimmune blistering diseases, as shown by recent studies of candidate genes expressed at different levels of the autoimmune process.

Systemic lupus erythematosus with celiac disease: a report of five cases.

Systemic lupus erythematosus and celiac disease (CD) are rarely reported in combination. We report five cases seen over a 4-year period. The two conditions occurred concomitantly in one patient, whereas the CD antedated the lupus in one patient and postdated the lupus in the remaining three patients. Villous atrophy on duodenal biopsy specimens with a favorable response to a gluten-free diet was noted in all five patients. Only four patients had positive serological tests for CD and only three had abdominal symptoms.

[Epidemiology of gram negative bacterial septicemias: data from a Tunisian hospital (1996-1998)]. / Epidémiologie des septicémies à bacilles gram négatif: données d'un hopital Tunisien (1996-1998).

Gram-negative bacilli (GNB) septicemia are among the most serious infections encountered in the hospital since they generally occur on debilitated patients and are due to the multi-drug resistant bacteria. A retrospective study relating to 195 septicemia was carried out with an aim studying epidemiologic profile, predisposing factors, entry sites for micro-organisms, responsible GNB and their antibiotic susceptibility. GNB septicemia were mainly frequent in intensive care units (34%) and surgery (31%). Previous antibiotherapy, invasive procedures and surgical acts were the principal predisposing factors. The entry sites for micro-organisms remained unknown in 1/3 of the cases. The most common source of septicemia was the urinary tract infections. E. coli was the most frequent isolated bacteria (26%) in the community acquired spticemia whereas Klebsiella-Enterobacter-Serratia (KES), Acinetobacter and Pseudomonas were mainly encountered in nosocomial infections. Imipenem remained the most active betalactamin on GNB (2% of resistance) with amikacin (16% of resistance) among aminoglycosides. The rate of mortality was 18%. Hospitalization wards (intensive care units, surgery), entry sites unknown, septic shock syndrome were the main factors of prognosis. The development of immunology and molecular biology should improve the outcome of these infections but the preventive measures remain the most effective.

New C1q mutation in a Tunisian family.

Hereditary C1q deficiency (C1qD) is the most penetrant genetic factor predisposing to the development of lupus pathology with more than 93% of C1q deficient patients developing this autoimmune pathology throughout their life. It is a rare autosomal recessive deficiency, with only 67 cases reported so far including one Tunisian girl who died at the age of three from complications resulting from severe systemic lupus erythematosus. Although C1qD was confirmed in the serum of this patient using C1q ELISA and classical pathway specific functional assays, no DNA sample had been obtained from this patient. Here we report the analysis of sera and DNA of members of this patient's closer family. Our analysis identified a homozygous mutation within the gene encoding the C-chain of C1q leading to a deficiency of C1q in an older sister of our original patient. This mutation, termed g.5580G4C, represents a single basepair substitution in exon 1 of the C1q C chain gene which changes the codon of Gly61 to Arg 61. Amongst the other 14 mutations leading to C1qD, g.5580G4C represents the first reported transversion leading to human C1qD.

Lichen planus pemphigoides: four new cases and a review of the literature.

Lichen planus pemphigoides (LPP) is a rare autoimmune blistering disease. It appears to be combination of lichen planus and bullous pemphigoid. We describe four new cases of LPP and discuss the epidemiological, clinical, pathological, and therapeutic features of this singular association through a review of the 74 published cases within the English literature. We report four cases of LPP (three women aged respectively 47, 51, and 53 years old, and a 53-year-old man). All patients presented with bullae on lichenoid and normal skin, predominately on the extremities. The diagnosis was confirmed by immunohistological findings. Our patients were treated with oral corticosteroids with a good response. Our review of the literature of 78 cases of LPP (65 adults and 13 children) showed that it involved adults (mean age: 54 years), with a slight female preponderance. A mean lag time between LP and the development of LPP was 8.3 months. LPP is characterized by developing blisters on lichenoid lesions and on uninvolved skin with more acral distribution of bullous lesions. Involvement of palms and soles was more frequent in children. The diagnosis is based on pathological and immunological confrontation. LPP is usually idiopathic, but some cases were reported in association with various drugs. There have also been reports of association with internal malignancy. Most cases of LPP are successfully treated with systemic corticosteroids. In most cases, the prognosis was good.

Autoimmune reactivity against precursor form of desmoglein 1 in healthy Tunisians in the area of endemic pemphigus foliaceus.

BACKGROUND: Desmoglein 1 (Dsg1), the pemphigus foliaceus (PF) antigen, is produced as a precursor (preDsg1) and is transported to the cell surface as the mature form (matDsg1). Recent studies show that B cells from North American individuals without pemphigus can potentially produce anti-preDsg1 IgG antibodies, but ELISA screening of large numbers of normal people in North America and Japan hardly ever shows circulating antibodies against preDsg1 or matDsg1. In contrast, in Tunisia, where PF is endemic, anti-Dsg1 IgGs are frequently detected in healthy individuals. OBJECTIVE: To characterize these anti-Dsg1 antibodies from normal individuals in Tunisia. METHODS: Sera from 16 healthy individuals and 9 PF patients in the endemic PF area in Tunisia, and sera from Japanese non-endemic PF patients were analyzed by immunoprecipitation-immunoblotting using recombinant proteins of preDsg1, matDsg1, and domain-swapped Dsg1/Dsg2 molecules. RESULTS: Sera from normal Tunisian individuals reacted to preDsg1 alone (8/16) or more strongly to preDsg1 than to matDsg1 (7/16), while those from all Tunisian PF patients and Japanese non-endemic PF patients reacted similarly to preDsg1 and matDsg1, or preferentially to matDsg1. The epitopes recognized by anti-Dsg1 IgGs from normal Tunisian individuals were more frequently found in the C-terminal extracellular domains (EC3 to EC5), while those in Tunisian endemic PF patients were more widely distributed throughout the extracellular domains, suggesting IgGs against EC1 and EC2 developed during disease progression. CONCLUSIONS: These findings indicate that IgG autoantibodies against Dsg1 are mostly raised against preDsg1 and/or C-terminal domains of Dsg1 in healthy Tunisians in the endemic area of PF.

What is the ability of anti-cyclic citrullinated peptide antibodies determination in synovial fluid in discriminating rheumatoid arthritis from non-rheumatoid arthritis patients? A Tunisian cross-sectional study.

Anti-cyclic citrullinated peptide antibodies (ACPA) seem to be produced locally at the site of joints inflammation in the first stage of rheumatoid arthritis (RA). A strong correlation between serum ACPA and ACPA in the synovial fluid (SF-ACPA) is now suggested. A case-control study was conducted to evaluate the usefulness of ACPA determination in SF of patients with RA. A total of 53 patients with a knee-joint effusion (26 RA, 18 peripheral spondyloarthropathies (SPA), and 9 osteoarthritis (OA)) were included in our study. SF samples were obtained by performing therapeutic arthrosynthesis. IgG serum ACPA and SF-ACPA levels were determined by the enzyme-linked immunosorbent assay (ELISA). We have also determined IgG levels in serum and SF by nephelometry. Higher levels of IgG ACPA antibodies in SF (p = 0.045) and serum (p = 0.045) were found in patients with RA with respect to SPA and OA patients. The Spearman correlation analysis showed a significant and positive correlation between ACPA in serum and SF (rho = 0.516; p = 0.007) not only in the RA group but also in patients with SPA. Serum ACPA discriminated RA from non-RA at a cut-off value of 2.7 U/ml (sensitivity, 69%; specificity, 78%; and area under the curve (AUC), 0.72), whereas SF-ACPA discriminated RA from non-RA at a higher cut-off value of 4.95 U/ml (sensitivity, 73%; specificity, 61%; and AUC, 0.71). Our study suggests that the determination of SF-ACPA give complement information to serum ACPA in patients with RA.