Non-autoimmune Diseases Research Articles

De novo autoimmune hepatitis following living-donor liver transplantation for primary biliary cirrhosis

Since first being described in 1998, de novo autoimmune hepatitis (AIH) after liver transplantation has been reported in several cases suffering from non-autoimmune liver diseases and primary biliary cirrhosis (PBC). Glutathione S-transferase (GST) T1 genotype mismatches between donor and recipient have also been suggested to constitute a risk factor for de novo AIH. Here, we report a 33-yr-old woman who presented complaining of marked fatigue and jaundice four yr after living-donor liver transplantation for PBC. On examination, transaminase levels were highly elevated and ANA and antimitochondrial antibody M2 were positive. Histological findings showed zonal necrosis with lymphoplasmacytic infiltration closely resembling AIH. She had pretreatment AIH score of 16 and 19 points after relapse of de novo AIH. Two color fluorescence in situ hybridization with X and Y chromosome-specific probes clearly revealed that the hepatocytes were of donor origin and lymphocytes were of patient origin. The GSTT1 genotype of the patient and the donor were the same null type, suggesting that mechanisms other than GSTT1 mismatches may exist in de novo AIH development. In conclusion, recipient immune cells attacked the allogeneic transplanted liver of the patient via de novo AIH, although the exact participation of autoimmune mechanisms is unclear.

Chronic unexplained anaemia in isolated autoimmune thyroid disease or associated with autoimmune related disorders

The prevalence of chronic unexplained anaemia was analysed in patients with autoimmune thyroid disease (ATD). The presence of chronic unexplained anaemia, defined as anaemia not related to evident or occult bleeding and/or to erythropoietic disorders, was retrospectively assessed and compared in patients with nonautoimmune thyroid disease (NATD) and in patients with ATD. Biochemical and morphological parameters of anaemia were investigated and characterized in 1643 consecutive Caucasian outpatients with thyroid disease. In 991 patients, thyroid disease had a nonautoimmune origin. ATD was diagnosed in 652 patients (71 had Graves' disease and 581 had Hashimoto's thyroiditis and its variants). In 145 patients ATD was associated with other autoimmune disorders. The presence of chronic unexplained anaemia was diagnosed in 123 patients (7.5%). Forty-eight had a thalassaemic trait, representing 2.9% of the whole sample. A true chronic unexplained anaemia was recorded in 75/1643 (4.6%). The occurrence of unexplained anaemia was similar in patients with NATD (1.9%) and in those with isolated ATD (2.96%; P = NS) but increased in patients with ATD and autoimmune related disorders (ARD) compared to patients with isolated ATD and/or with NATD (28.3%; both P < 0.0001; RR = 9.56 and 14.75, respectively). Chronic unexplained anaemia was virtually absent in hyperthyroid patients and was more prevalent in hypothyroid than in euthyroid patients with ATD (P = 0.0047; RR = 2.104). These results indicate that the increased frequency of chronic anaemia in patients with ATD is essentially due to the presence of concomitant autoimmune gastrointestinal diseases.

CD4 +CD25 + naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2 h4 mice

NOD-H2 h4 mice, which express I-A k on the NOD background, spontaneously develop autoimmune thyroiditis, a model of Hashimoto thyroiditis in humans, by adding iodide in the drinking water. Parental NOD mice have previously been shown to have intrinsic numerical abnormalities in peripheral lymphocytes and lymphocyte subpopulations such as CD4 +CD25 + naturally occurring regulatory T cells (Treg). Therefore we first investigated whether the similar abnormalities exist in NOD-H2 h4 mice. We observed that, compared with other non-autoimmune disease prone BALB/c and C57BL/6 mice, NOD-H2 h4 mice have lower numbers of splenocytes, CD3 +T, CD4 +T and CD8 +T cells but the ratios of Treg to CD4 +T cells were comparable. Increasing the numbers of peripheral lymphocytes by Complete Freund's Adjuvant immunization or splenocyte transfer did not affect development of thyroiditis, indicating that lymphopenia does not play a critical role in the pathogenesis of thyroiditis. We next examined the significance of Treg by depleting this lymphocyte subset with anti-CD25 antibody. Treg depletion, performed 4 days before the administration of NaI water for 8 weeks, significantly exacerbated thyroiditis ( p < 0.01). Anti-thyroglobulin antibody titers also increased by Treg depletion ( p < 0.01) without changing the IgG2b to IgG1 ratios. In addition, expression levels of mRNA for IFN-γ and IL-4 were enhanced in parallel. However, T 4 levels were similar between antibody-treated and untreated groups. Additional anti-CD25 administration at 3 weekly intervals did not influence these results. These data, together with previous studies on other mouse models of inducible thyroiditis and Graves’ disease, indicate the role played by Treg in keeping anti-thyroid autoimmune reaction in check in experimental autoimmune thyroid diseases.

Thyroid function and anti‐thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection

The reported data on thyroid function and anti-thyroid autoantibodies in adults with untreated hepatitis C virus (HCV) infection are controversial. Data are scarce for HCV-infected children, and only in those treated with interferon-alpha (IFN-alpha). We investigated thyroid function and anti-thyroid autoantibodies in a cohort of untreated children with vertically acquired, chronic, HCV infection. FT4 and TSH serum levels (measured by immunometric assays) and anti-thyroglobulin (TgA) and anti-thyroperoxidase (TPOA) antibodies (evaluated by fluorescence enzymatic immunoassays) were studied in 36 consecutive HCV-infected children and 150 age- and sex-matched controls. The prevalence of thyroid involvement was also related to family history of autoimmune disease, distribution of HCV genotypes, and duration and activity of HCV infection. Four out of 36 (11.1%) HCV-infected children and 4/150 controls (2.7%) showed subclinical hypothyroidism [P = 0.04; relative risk (RR) 4.56, 95% confidence interval (CI) 1.08-19.21]. None of these had anti-thyroid autoantibodies. Two out of 36 (5.6%) HCV-infected children and 1/150 (0.7%) controls had increased TgA values with normal levels of TSH (P > 0.05). Subclinical hypothyroidism and anti-thyroid autoantibodies were not related to family history of autoimmune disease, duration of infection, HCV viral load, liver function or different HCV genotype distribution, but seemed to be related to the presence of active HCV infection. Our data suggest a role for HCV infection in the development of nonautoimmune thyroid disease in untreated HCV-infected children, confirming previous studies in adults. Clinicians should be aware of thyroid dysfunction even in untreated children.

Interleukin‐6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus

To define the cytokine and chemokine profile in cerebrospinal fluid (CSF) from patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Forty-two SLE patients who had been hospitalized because of NP manifestations were studied. Patients were evaluated at hospitalization and 6 months later; a CSF sample was obtained at each evaluation. As controls, CSF from 6 SLE patients with septic meningitis, 16 SLE patients with no history of NP manifestations (non-NPSLE), and 25 patients with nonautoimmune diseases were also studied. Soluble molecules, including cytokines (interleukin-2 [IL-2], IL-4, IL-6, IL-10, tumor necrosis factor alpha [TNFalpha], and interferon-gamma [IFNgamma]) and chemokines (monocyte chemotactic protein 1 [MCP-1], RANTES, IL-8, monokine induced by IFNgamma [MIG], and interferon-gamma-inducible 10-kd protein [IP-10]), were measured with the use of cytometric bead array kits. CSF levels of the following molecules were significantly increased in NPSLE patients as compared with non-NPSLE and nonautoimmune diseases control patients, respectively: IL-6 (32.7 versus 3.0 and 2.96 pg/ml), IL-8 (102.8 versus 29.97 and 19.7 pg/ml), IP-10 (888.2 versus 329.7 [P not significant] and 133.6 pg/ml), RANTES (3.8 versus 2.5 and 2.2 pg/ml), MCP-1 (401.7 versus 257.9 [P not significant] and 136.9 pg/ml), and MIG (35.4 versus 11.4 and 3.5 pg/ml). Low levels of IL-2, IL-4, IL-10, TNFalpha, and IFNgamma were found in all groups. All cytokines and chemokines, except TNFalpha, were significantly higher among the SLE patients with septic meningitis than among the NPSLE patients. Six months later and in the absence of NP manifestations, all elevated molecule levels, except RANTES, in patients with NPSLE had decreased significantly, and no differences were noted between the NPSLE and non-NPSLE groups. A central nervous system response composed of IL-6 and chemokines, but not Th1/Th2 cytokines, is associated with NP manifestations in SLE patients.

Prevalence and Functional Significance of Antipituitary Antibodies in Patients with Autoimmune and Non-Autoimmune Thyroid Diseases

Circulating antipituitary antibodies (APA) are markers of autoimmune hypophysitis, which may cause deficient pituitary function. The prevalence of APA in autoimmune thyroid disorders (AITD) is uncertain. The aims of this study were 1) to evaluate APA prevalence in a large series of patients with AITD and non-AITD and 2) to investigate the functional significance of APA by assessing pituitary function in APA-positive patients. We conducted a health survey on consecutive AITD and non-AITD patients at a tertiary referral center (Department of Endocrinology, Pisa). Subjects, including 1290 consecutive patients with thyroid disorders (961 AITD and 329 non-AITD) and 135 controls, were enrolled in the study. APA (indirect immunofluorescence), free T(4), free T(3), TSH, and organ-specific autoantibodies were assayed in all patients. Functional pituitary evaluation was performed in most APA-positive patients. APA frequency was higher in AITD (11.4%) than in non-AITD (0.9%; P < 0.0001) patients; all control subjects had negative APA tests. APA were more frequently found in Hashimoto's thyroiditis (13%) than in Graves' disease (7.1%; P = 0.05). Of 110 APA-positive AITD patients, 20 (18.2%) had autoimmune polyglandular syndrome, whereas 90 (81.8%) had apparently isolated AITD. APA positivity increased percentage of autoimmune polyglandular syndrome in our series from 10.4 to 13.5%. Of 110 APA-positive patients, 102 were submitted to dynamic testing for functional pituitary assessment; 36 patients (35.2%) had mild or severe GH deficiency (GHD). No additional anterior pituitary hormone deficiencies were found; one patient had central diabetes insipidus. Pituitary abnormalities at magnetic resonance imaging were found in most APA-positive GHD patients. APA are frequently present in patients with AITD. Patients should be tested for APA because positive tests are associated with GHD.

Some Recent Insights into the Prothrombogenic Mechanisms of Antiphospholipid Antibodies

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies, detected in the sera of patients with both autoimmune and various non-autoimmune diseases. They are also detected in subjects with no overt underlying disease - the primary antiphosphilipid syndrome (PAPS). High titers of APL are associated with arterial and venous thrombosis, recurrent fetal loss and thrombocytopenia. There have been many suggestions explaining the potential mechanisms of the procoagulant effect of aPL. These include endothelial cell (EC) activation; increased adhesion molecule expression; inhibition of EC prostacyclin release, increased leucocyte adhesion to EC, downregulation of thrombomodulin expression. APL induce the procoagulant activity of monocytes via increased tissue factor expression and directly stimulate platelet hyperactivity with resultant production of enhanced amounts of the proaggregatory molecule of TXA(2). In vitro studies show that prepro-endothelin-1 mRNA is induced by human monoclonal anticardiolipin antibodies and this might contribute to vasospasm, and, ultimately, to arterial occlusion. The hypercoagulable state in APS patients is associated with alterations in the protein C/S pathway. It is suggested that aPL may impair the protein C anticoagulant system. Acquired protein C and protein S deficiency is described in patients with APS. Beta2- glycoprotein I, (Beta2-GPI) a natural anticoagulant, is involved in the regulation of protein S anticoagulant activity by preventing the binding of protein S to C4b-binding protein. APL were shown to inhibit this effect of Beta2- GP I. As the group of aPL is very heterogeneous, it is unlikely that a single mechanism is responsible for the thrombogenic activity of all aPLs associated with thrombosis.

Using Desmoglein 1 and 3 Enzyme-linked Immunosorbent Assay as an Adjunct Diagnostic Tool for Pemphigus

Pemphigus is an acquired autoimmune intraepidermal blistering disease that is divided into 2 major subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Patients with pemphigus have circulating anti-desmoglein (Dsg)1 and/or anti-Dsg3 IgG autoantibodies. Recently, a novel commercial enzyme-linked immunosorbent assay (ELISA) against Dsg1 and Dsg3 has been established and found to be extremely sensitive and specific. To date, the usefulness of Dsg1 and Dsg3 ELISA in the diagnosis of pemphigus in the Taiwanese population has never been reported. Serum samples were obtained from 143 patients, including 20 patients with PV, 9 patients with PF, 72 patients with bullous pemphigoid, 1 patient with dermatitis herpetiformis and 41 patients with non-autoimmune blistering diseases. They were tested for anti-Dsg1 and anti-Dsg3 reactivity by ELISA. Seventeen of 20 PV sera (85%) exceeded the cut-off value of Dsg3 ELISA, and 9 of 9 PF sera (100%) exceeded the cut-off value of Dsg1 ELISA, while only 1 (0.88%) and 3 (2.6%) of 114 non-pemphigus sera exceeded the cut-off values of Dsg3 and Dsg1 ELISAs, respectively. Thus, the sensitivity and specificity of Dsg3 ELISA were 85% and 99.1%, while the sensitivity and specificity of Dsg1 ELISA were 100% and 97.4%, respectively. The correlation between ELISA scores and disease activity along the time course was examined in 6 PV patients and 1 PF patient, and the result was equivocal. Dsg1 and Dsg3 ELISAs provide a simple, highly sensitive and specific method that can serve as a useful adjunct tool for the initial diagnosis of pemphigus.

Human leukocyte antigen and adult living-donor liver transplantation outcomes: An analysis of the organ procurement and transplantation network database

Human leukocyte antigen (HLA) compatibility has no clinically significant impact in cadaveric liver transplantation. Less is known regarding living-donor liver transplantation (LDLT). Our prior analysis of the Organ Procurement and Transplantation Network (OPTN) database suggested a higher graft failure rate in patients who underwent LDLT from donors with close HLA match. We further investigated the effect of HLA-A, -B, and -DR matching on 5-yr graft survival in adult LDLT by analyzing OPTN data regarding adult LDLT performed between 1998 and 2005. We evaluated associations between 5-yr graft survival and total, locus-specific, and haplotype match levels. Separate analyses were conducted for recipients with autoimmune (fulminant autoimmune hepatitis, cirrhosis secondary to autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) or nonautoimmune liver disease. Multivariable Cox proportional hazard models were used to evaluate interactions and adjust for potential confounders. Among 631 patients with available donor/recipient HLA data, the degree of HLA match had no significant effect on 5-yr graft survival, even when analyzed separately in recipients with autoimmune vs. nonautoimmune liver disease. To be able to include all 1,838 adult LDLTs, we considered a first-degree related donor as substitute for a close HLA match. We found no difference in graft survival in related vs. unrelated pairs. In conclusion, our results show no detrimental impact of close HLA matching on graft survival in adult LDLT, including in recipients with underlying autoimmune liver disease.

Antibodies against Calsequestrin and Type XIII Collagen are Good Markers for Chronic Upper Eyelid Retraction

Purpose: Chronic upper eyelid retraction is a common manifestation of thyroid-associated ophthalmopathy (TAO) but can occur as a dominant feature of ophthalmopathy in patients with Graves’ hyperthyroidism and in association with Hashimoto's thyroiditis in the absence of other eye signs except mild proptosis. Methods: We measured antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in an enzyme-linked immunosorbent assay (ELISA) in 15 patients with chronic upper eyelid retraction. Results: Calsequestrin antibodies were detected in 67% of patients with upper eyelid retraction, Fp antibodies in 47%, G2s antibodies in 20%, and collagen XIII antibodies were detected in 40% of these patients at the first visit. These prevalences were significantly greater than normal for calsequestrin and collagen XIII, but not for Fp and G2s antibodies. On follow-up, calsequestrin antibodies were detected in two more patients, for an overall prevalence of 80%. Levels of the four antibodies remained fairly constant over the study period and generally correlated with the presence and severity of upper eyelid signs. Conclusions: These findings support the notion that autoimmune attack against calsequestrin and collagen XIII in the levator palpebrae superioris (LPS) muscle may play a role in the pathogenesis of upper eyelid retraction and that lid retraction may be the dominant feature of ophthalmopathy in patients with Hashimoto's thyroiditis and non-autoimmune thyroid disease. Because calsequestrin is an intracellular protein, the corresponding autoantibodies probably do not initiate LPS muscle inflammation but may contribute to its damage. The mix of antibodies against calsequestrin and collagen XIII may shed light on the diverse presentations found in thyroid-associated ophthalmopathy.

Carbonic anhydrase III: A new target for autoantibodies in autoimmune diseases

The objective of this study was to identify new autoantibodies that could be useful for the diagnosis of rheumatoid arthritis (RA) using immunoblotting on synovial membrane proteins which represent the best source of candidate RA autoantigens. A new target protein with a molecular weight of 26 kDa was found to be recognized by autoantibodies in RA sera and was identified using MALDI-TOF mass spectrometry and second-dimension electrophoresis as carbonic anhydrase III (CAIII). Three similar protein spots at 26 kDa were recognized by both human sera and monoclonal antibody (mAb) directed against CAIII on immunoblotting using the human recombinant CAIII. Interestingly, CAIII expression within the synovial membrane was not observed in non-RA patients and was differentially expressed among RA patients. The sensitivity of these new autoantibodies for RA, using an immunoenzymatic technique, was 17%. Specificity was high when comparing non-autoimmune diseases (100%), while it was found to be weak (67%) when comparing some other autoimmune diseases, and particularly systemic lupus erythematosus (SLE). In conclusion, this study demonstrates that these new autoantibodies against CAIII are not restricted to RA. However the expression of CAIII in the synovial membrane of RA warrants further investigation of the pathophysiological relevance of this finding.

Introduction to the use of the Boston keratoprosthesis

The Boston keratoprosthesis (KPro) is one of several types of artificial cornea manufactured worldwide that are being implanted in increasing numbers in patients with severe corneal diseases and graft failures. The prognosis for long-term success varies greatly between diseases, with autoimmune conditions, such as ocular cicatricial pemphigoid and Stevens–Johnson syndrome, and severe chemical burns remaining difficult. In the potentially much larger cohort with little preoperative inflammation, retention is excellent, complications are manageable and outcome is usually very good. Early implantation in congenital corneal opacities to offset amblyopia shows promise. The Boston KPro uses a ‘collar button’ design of polymethyl methacrylate that is sturdy and easily machined and polished, giving excellent vision if the remainder of the eye is healthy. This is implanted into a carrier corneal graft or into the patient’s own cornea. Holes in the back plate allow nutrition from the aqueous humor to reach the graft and long-term use of around-the-clock soft contact lenses protects the ocular surface from excessive dehydration. In nonautoimmune diseases, these measures have virtually eliminated necrosis and melt of the corneal tissue holding the device. Postoperative prophylactic antibiotics can now fully protect eyes from infection.

Nonclassic Congenital Lipoid Adrenal Hyperplasia: A New Disorder of the Steroidogenic Acute Regulatory Protein with Very Late Presentation and Normal Male Genitalia

Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and gonadal steroidogenesis caused by mutations in the steroidogenic acute regulatory protein (StAR). Affected children typically present with life-threatening adrenal insufficiency in early infancy due to a failure of glucocorticoid (cortisol) and mineralocorticoid (aldosterone) biosynthesis, and 46,XY genetic males have complete lack of androgenization and appear phenotypically female due to impaired testicular androgen secretion in utero. The objective of this study was to investigate whether nonclassic forms of this condition exist. Sequence analysis of the gene encoding StAR was undertaken in three children from two families who presented with primary adrenal insufficiency at 2-4 yr of age; the males had normal genital development. Identified mutants were tested in a series of biochemical assays. DNA sequencing identified homozygous StAR mutations Val187Met and Arg188Cys in these two families. Functional studies of StAR activity in cells and in vitro and cholesterol-binding assays showed these mutants retained approximately 20% of wild-type activity. These patients define a new disorder, nonclassic lipoid congenital adrenal hyperplasia, and represent a new cause of nonautoimmune Addison disease (primary adrenal failure).

Relationship of Anti-vimentin antibodies to anti-endothelial antibodies

Abstract The intermediate filament protein vimentin is a potential target antigen for autoantibodies in some infectious and autoimmune diseases. Because endothelial cells contain an extensive interconnecting cytoplasmic network of vimentin, we examined the relationship between anti-vimentin and anti-endothelial cell antibodies (AECAs). We measured the level of anti-vimentin antibodies in patients with systemic autoimmune diseases (n=42), healthy blood donors (n=58), and patients with acute inflammation and showing anti-vimentin immunofluorescence (n=50). AECAs were detected by indirect immunofluorescence in human umbilical vein endothelial cells. Anti-vimentin antibodies were detected by indirect immunofluorescence in HEp-2 cells, and levels of anti-vimentin antibodies were measured using an enzyme-linked immunosorbent assay. We did not find significant differences in anti-vimentin levels between AECA-positive and-negative samples for any of the groups; however, serum anti-vimentin antibody levels were significantly higher in patients with acute non-autoimmune inflammatory diseases than in patients with systemic autoimmune diseases or healthy controls. There were no differences between the levels of anti-vimentin antibodies between patients with systemic autoimmune diseases and healthy individuals. The anti-vimentin antibodies levels also did not correlate with the AECA positivity.

Tissue transglutaminase ELISA positivity in autoimmune disease independent of gluten-sensitive disease

BackgroundOur aim was to understand why some sera from patients with a broad spectrum of autoimmune diseases or non-autoimmune diseases involving enhanced apoptosis, cell lysis and/or putative secondary autoimmune processes show reactions in the tissue transglutaminase (TGc) ELISA used for diagnosis of gluten-sensitive disease. MethodsSera were compared from groups of patients with autoimmune diseases, diseases involving organ specific enhanced cell death, celiac disease or dermatitis herpetiformis, diseases of non-autoimmune origin, and a group without known disease. IgA antibodies against TGc were detected using human antigen (produced recombinantly in bacterial or human cells) in different systems (non-commercial ELISA with buffers of differing NaCl concentrations, and anti-TGc sandwich ELISA). Anti-gliadin and anti-endomysium antibodies were also determined. ResultsMany sera from patients with autoimmune disorders gave a positive signal in the human TGc ELISAs. The signal appeared related to minor impurities in the recombinant human TGc used and to raised serum IgA antibody levels rather than to the occurrence of TGc specific antibodies in these patients. ConclusionsNo association of anti-TGc Abs and autoimmune conditions independent of gluten-sensitive disease could be shown. Care should be taken to exclude copurification of chaperones, like heat shock protein 70, where preparing antigens for TGc ELISAs.

Clinic-Cytologic Study of Conjunctivochalasis and Its Relation to Thyroid Autoimmune Diseases

To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases, to determine whether there is any association between the 2 diseases, and to determine cytologic study of conjunctivochalasis through the cytology impression test. A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP). The patients included were divided into 2 groups following these inclusion criteria: a control group of 25 patients without thyroid diseases, confirmed after clinical and laboratory examinations (thyroid hormones), or any other ocular diseases. The study group consisted of 31 patients with thyroid diseases, the diagnosis of which was confirmed by the Endocrinology Sector. The thyroidopathies included were autoimmune diseases but excluded nonautoimmune diseases. A protocol endorsed by the UNIFESP was followed, using clinical and ophthalmological history, biomicroscopy, and impression cytology. Fifty-two percent of patients without thyroid diseases and 88% of patients with thyroid diseases presented with conjunctivochalasis. The risk ratio was 1.705 (Pr > chi(2) = 0.0038), indicating that there is an association between them. For the impression cytology in inferior bulbar conjunctiva, there was an association between the result of the impression cytology and conjunctivochalasis (Pearson chi(2) = 10.1190 Pr = 0.006). The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88%. Patients with autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group, confirming the association between them. The cytologic study showed the highest prevalence of abnormal surface features in eyes with conjunctivochalasis.

Immunity to Extracellular Matrix Antigens is Associated with Ultrastructural Alterations of the Stroma and Stratified Epithelium Basement Membrane in the Skin of Hashimoto's Thyroiditis Patients

Employing purified extracellular matrix (ECM) proteins, i.e. type I, III, IV and V collagens (CI, CIII, CIV, CV), laminin (LM) and fibronectin (FN), as antigen sources we detected autoantibodies to conformational and/or denatured ECM antigens among 34 of 50 sera obtained from Hashimotos thyroiditis (HT) patients and 6 of 51 control sera obtained from non-autoimmune thyroid disease patients and healthy donors (HT sera vs. control sera p=4 x 10-9). Reactivity to conformational antigens, mostly due to autoantibodies of the IgG isotype, was observed in 30/50 HT sera and in 6/51 control sera (p=3.5 x 10-7) and was not always concomitant with that to linear antigens, found in 23/50 HT and in 6/51 control sera (p=1.6 x 10-4). Ultrastructural analysis of skin biopsies obtained from 18 HT patients without symptomatic cutaneous diseases revealed defects of the stratified squamous epithelium basement membrane in 11/18, alterations of the stroma in 13/18 and both basement membrane and stromal defects in 9/18. Interestingly, 13/13 (p=0.012) and 9/11 (p=0.012) patients with stromal and basement membrane defects respectively, exhibited serum antibodies to at least one ECM antigen involved in the organization of the altered tissue compartment. Lastly, 10/18 skin biopsies presented immunoglobulin (Ig) and/or complement (C3) deposits along the cutaneous basement membrane zone (BMZ) or in the papillary dermis and 9/10 sera from the same patients simultaneously showed antibodies to at least one ECM antigen involved in the organization of these two skin compartments. Besides, 8/11 HT patients with basement membrane defects exhibited Ig or C3 deposits along the BMZ. Our findings suggest that autoantibodies to ECM molecules might contribute to the development of asymptomatic extra-thyroid skin diseases in HT patients.

Estimated Risk for Developing Autoimmune Addison’s Disease in Patients with Adrenal Cortex Autoantibodies

Patients with adrenal cortex autoantibodies (ACA) without overt autoimmune Addison's disease (AAD) are at risk of adrenal failure. To assess the contribution of different clinical, immunological, genetic, and functional factors in the progression to AAD, we followed up 100 ACA-positive and 63 ACA-negative patients without AAD for a maximum of 21 yr (mean 6.0 yr, median 4.8). ACA were measured by immunofluorescence and 21-OH autoantibodies (Abs) by RIA. Adrenal function was assessed by measuring basal levels of cortisol, aldosterone, ACTH, renin activity, and cortisol response to ACTH. The risk of developing AAD was calculated using survival and multivariate analyses. AAD developed in 31 ACA-positive patients and one ACA-negative patient. The cumulative risk of disease in ACA-positive patients was 48.5% [95% confidence interval (CI) 40.8-56.1]. The cumulative risk was higher in children than adults (100 vs. 31.9%; P < 0.0001), males than females (68.6 vs. 42.7%; P = 0.006), patients with subclinical rather than normal adrenal function at entry (87.4 vs. 30.1%; P < 0.0001), patients with hypoparathyroidism and/or candidiasis than patients with other autoimmune or nonautoimmune diseases (100 vs. 29.7%; P < 0.0001), and patients with high rather than low-medium ACA titers (62.8 vs. 41.2%; P = 0.12). The presence of human leukocyte antigen (HLA)-DRB1 did not appear to contribute to the prediction of AAD. Adjusted hazard ratios by Cox model for the development of AAD were 3.37 for males (CI 1.38-8.24), 5.23 for hypoparathyroidism and/or candidiasis (CI 1.53-17.92), 3.33 for high antibody titers (CI 1.43-7.78), and 6.15 for impaired adrenal function at entry (CI 2.79-13.57). These results were used to construct a risk algorithm for estimating the probability of developing AAD from the combination of gender, age, adrenal function, antibody titer, and associated autoimmune disorders at entry. The values of estimated risk could be used to decide appropriate follow-up intervals and future immunointervention strategies.

Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-β) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-β, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.

Systemic lupus erythematosus following virological response to peginterferon alfa-2b in a transplanted patient with chronic hepatitis C recurrence

Autoimmune manifestations are common both in patients chronically infected by hepatitis C virus, and in patients transplanted for non-autoimmune diseases. A correlation between interferon based treatment and autoimmune diseases or the development of autoantibodies is well established in non-transplanted patients, but few data are available about transplanted patients. It is unclear whether interferon may increase the incidence of acute cellular rejection and there are few reports on the development of atypical autoimmune manifestations during post-liver transplantation interferon or pegylated interferon treatment. We describe a case of systemic lupus erythematosus following treatment with pegylated interferon alfa-2b in a transplanted patient with recurrence of chronic hepatitis C. Our experience suggest that pegylated interferon may induce autoimmune diseases in the immunosuppressed host, different from acute cellular rejection and call for a great attention to possible autoimmune disorders development during interferon based treatments in liver transplanted patients.