A genotype-phenotype correlation matrix for ABCA4 disease based on long-term prognostic outcomes.

BackgroundMore than 1500 variants in the ATP-binding cassette, sub-family A, member 4 (ABCA4), locus underlie a heterogeneous spectrum of retinal disorders ranging from aggressive childhood-onset chorioretinopathy to milder late-onset macular disease. Genotype-phenotype correlation studies have been limited in clinical applicability as patient cohorts are typically small and seldom capture the full natural history of individual genotypes. To overcome these limitations, we constructed a genotype-phenotype correlation matrix that provides quantifiable probabilities of long-term disease outcomes associated with specific ABCA4 genotypes from a large, age-restricted patient cohort.MethodsThe study included 112 unrelated patients at least 50 years of age in whom 2 pathogenic variants were identified after sequencing of the ABCA4 locus. Clinical characterization was performed using the results of best corrected visual acuity, retinal imaging, and full-field electroretinogram testing.ResultsFour distinct prognostic groups were defined according to the spatial severity of disease features across the fundus. Recurring genotypes were observed in milder prognoses, including a newly defined class of rare hypomorphic alleles. PVS1 (predicted null) variants were enriched in the most severe prognoses; however, missense variants were present in a larger-than-expected fraction of these patients. Analysis of allele combinations and their respective prognostic severity showed that certain variants, such as p.(Gly1961Glu), and both rare and frequent hypomorphic alleles, were "clinically dominant" with respect to patient phenotypes irrespective of the allele in trans.ConclusionThese results provide much-needed structure to the complex genetic and clinical landscape of ABCA4 disease and add a tool to the clinical repertoire to quantitatively assess individual genotype-specific prognoses in patients.FUNDINGNational Eye Institute, NIH, grants R01 EY028203, R01 EY028954, R01 EY029315, P30 19007 (Core Grant for Vision Research); the Foundation Fighting Blindness USA, grant no. PPA-1218-0751-COLU; and Research to Prevent Blindness.

Detection of Toxoplasma gondii bradyzoite genes in the peripheral blood mononuclear cells among patients with toxoplasmic chorioretinitis.

BACKGROUND: Toxoplasmic chorioretinitis may occur as a result of acquired toxoplasmosis or reactivated congenital toxoplasmosis. In this study, Toxoplasma gondii bradyzoite genes along with the B1 gene were evaluated to detect T. gondii DNA in serum and peripheral blood mononuclear cells (PBMCs) of patients with toxoplasmic chorioretinitis. METHODS: Blood samples were collected from 10 patients (7 cases of active chorioretinal lesions and 3 cases of old chorioretinal scars). The genomic DNA was extracted from the patients' serum and PBMCs and a polymerase chain reaction (PCR) assay was performed using bradyzoite genes along with B1. The subjects were also evaluated in terms of the T. gondii antibodies. RESULTS: The PCR results were positive in four of seven patients (57.1%) with active ocular toxoplasmosis lesions. In three patients (42.8%), the PCR results were positive for MAG-1 and SAG-4 and in one patient (14.3%) the PCR results were only positive for the B1 gene. The PCR results were positive only in the PBMCs, whereas they were negative in the serum samples. Two patients with positive PCR results showed high Toxoplasma immunoglobulin G (IgG) antibody titres. However, none of the patients showed positive Toxoplasma IgM antibodies. CONCLUSIONS: The PBMCs are suitable for evaluating toxoplasmic chorioretinitis. The present results showed that PCR with bradyzoite genes is useful in the diagnosis of toxoplasmic chorioretinitis in PBMCs.

Toxoplasmic retinochoroiditis: The influence of age, number of retinochoroidal lesions and genetic polymorphism for IFN-γ +874 T/A as risk factors for recurrence in a survival analysis.

PURPOSE: To analyze risk factors for recurrent toxoplasmic retinochoroiditis. DESIGN: Single center prospective case series. POPULATION AND METHODS: A total of 230 patients with toxoplasmic retinochoroiditis were prospectively followed to assess recurrences. All patients were treated with a specific drug regime for toxoplasmosis in each episode of active retinochoroiditis. Individuals with chronic diseases and pregnant women were excluded. Survival analysis by extended Cox regression model (Prentice-Williams-Peterson counting process model) was performed to evaluate the time between recurrences according to some potential risk factors: age, number of retinochoroidal lesions at initial evaluation, sex and interferon gamma +874 T/A gene polymorphism. Hazard Ratios (HR) and 95% confidence intervals (CI) were provided to interpret the risk effects. RESULTS: One hundred sixty-two recurrence episodes were observed in 104 (45.2%) patients during follow-up that lasted from 269 to 1976 days. Mean age at presentation was 32.8 years (Standard deviation = 11.38). The risk of recurrence during follow up was influenced by age (HR = 1.02, 95% CI = 1.01-1.04) and number of retinochoroidal lesions at the beginning of the study (HR = 1.60, 95% CI = 1.07-2.40). Heterozygosis for IFN-γ gene polymorphism at position +874 T/A was also associated with recurrence (HR = 1.49, 95% CI = 1.04-2.14). CONCLUSION: The risk of ocular toxoplasmosis recurrence after an active episode increased with age and was significantly higher in individuals with primary lesions, which suggests that individuals with this characteristic and the elderly could benefit from recurrence prophylactic strategies with antimicrobials. Results suggest an association between IFN-γ gene polymorphism at position +874T/A and recurrence.

Clinical and Biological Factors Associated With Recurrences of Severe Toxoplasmic Retinochoroiditis Confirmed by Aqueous Humor Analysis.

PURPOSE: To investigate clinical and biological factors influencing recurrences of severe toxoplasmic retinochoroiditis (TRC) confirmed by aqueous humor analysis. DESIGN: Retrospective case series. METHODS: Retrospective analysis of 87 subjects with severe TRC, proven by positive Goldmann-Witmer coefficient (GWC), Toxoplasma gondii (T. gondii) immunoblot, or T. gondii-specific polymerase chain reaction (PCR) in aqueous humor. Cases with immunosuppression or retinal scars without previous recorded episode were excluded. Time-dependent, clinical, treatment-related, and biological factors were explored by univariate and multivariate shared frailty survival analyses. RESULTS: Among 44 included subjects (age, 40.4 ± 17.6 years; follow-up, 8.3 ± 2.7 years), 22 presented recurrences. There was 0.11 recurrence/patient/year and mean disease-free interval was 5.0 ± 2.9 years. The risk of recurrence was higher immediately after an episode (P < .0001). Among recurrent cases, the risk of multiple recurrences was higher when the first recurrence occurred after longer disease-free intervals (P = .046). In univariate analysis, the recurrence risk declined with higher number of intense bands on aqueous T. gondii immunoblot (P = .006), and increased when venous vasculitis was present initially (P = .019). Multivariate analysis confirmed that eyes with more intense bands on immunoblot had fewer recurrences (P = .041). There was a near-significant risk elevation after pyrimethamine/azithromycin treatment (P = .078 and P = .054, univariate and multivariate). Intravenous corticosteroid administration, oral corticosteroid administration, aqueous GWC, and T. gondii PCR did not influence recurrences (P = .12, P = .10, P = .39, and P = .96, respectively). CONCLUSIONS: Recurrences of severe TRC are not random and may be influenced by clinical and biological factors possibly related to blood-retinal barrier alterations. These results may contribute to identifying biomarkers for TRC reactivation.

How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins.

Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behçet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter-dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes.

Allele-specific Alterations in the Peptidome Underlie the Joint Association of HLA-A*29:02 and Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) with Birdshot Chorioretinopathy.

Virtually all patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. To investigate the relationship between both risk factors we employed label-free quantitative mass spectrometry to characterize the effects of ERAP2 on the A*29:02-bound peptidome. An ERAP2-negative cell line was transduced with lentiviral constructs containing GFP-ERAP2 or GFP alone, and the A*29:02 peptidomes from both transduced cells were compared. A similar analysis was performed with two additional A*29:02-positive, ERAP1-concordant, cell lines expressing or not ERAP2. In both comparisons the presence of ERAP2 affected the following features of the A*29:02 peptidome: 1) Length, with increased amounts of peptides >9-mers, and 2) N-terminal residues, with less ERAP2-susceptible and more hydrophobic ones. The paradoxical effects on peptide length suggest that unproductive binding to ERAP2 might protect some peptides from ERAP1 over-trimming. The influence on N-terminal residues can be explained by a direct effect of ERAP2 on trimming, without ruling out and improved processing in concert with ERAP1. The alterations in the A*29:02 peptidome suggest that the association of ERAP2 with BSCR is through its effects on peptide processing. These differ from those on the ankylosing spondylitis-associated HLA-B*27. Thus, ERAP2 alters the peptidome of distinct HLA molecules as a function of their specific binding preferences, influencing different pathological outcomes in an allele-dependent way.

Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3-Mutant Dogs.

Achromatopsia is an inherited retinal disorder of cone photoreceptors characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. Approximately 50% of cases are caused by mutations in the cone photoreceptor-specific cyclic nucleotide gated channel beta subunit (CNGB3) gene. Studies in CNGB3-mutant dogs showed that subretinal injection of an AAV vector expressing human CNGB3, which has 76% amino acid identity with canine CNGB3, driven by a 2.1 kb human red cone opsin promoter (PR2.1) and packaged in AAV5 capsids (AAV5-PR2.1-hCNGB3) rescued cone photoreceptor function, but at high doses was associated with an inflammatory response (focal chorioretinitis) consistent with immune-mediated toxicity. AAV vectors containing the PR2.1 promoter packaged in AAV5 capsids and expressing either the native canine CNGB3 (AAV5-PR2.1-cCNGB3) or the human CNGB3 (AAV5-PR2.1-hCNGB3) were evaluated at different dose levels in CNGB3-mutant dogs. The vector expressing canine CNGB3 achieved somewhat better rescue of cone function but unexpectedly was associated with a greater degree of retinal toxicity than the vector expressing human CNGB3. Very low-level T-cell immune responses to some AAV or CNGB3 peptides were observed in animals that received the higher vector dose. There was a more than twofold increase in serum neutralizing antibodies to AAV in one of three animals in the low-dose group and in two of three animals in the high-dose group. No serum anti-hCNGB3 antibodies were detected in any animal. The results of this study do not support the hypothesis that the focal chorioretinitis seen with high doses of AAV5-PR2.1-hCNGB3 in the initial studies was due to an immune response to human CNGB3.

Associations between Polymorphisms within Interferon Gamma and Tumor Necrosis Factor Genes and Toxoplasma Retinochoroiditis in Ghanaian Patients.

PURPOSE: To evaluate associations between IFN-γ +874T/A and TNF-α-308G/A polymorphism with the development of Toxoplasma retinochoroiditis. METHODS: By ARMS-PCR, a cross-sectional genetic study involving 30 patients with Toxoplasma retinochoroiditis and 87 controls was carried out. RESULTS: IFN-γ +874: by comparing with the AA genotype, individuals with the TT genotype had a 3.4 odds ratio (OR); AT had a 1.6 OR; and the T allele had a higher OR (1.6), indicating a likely susceptibility of IFN-γ +874T to the infection, though the overall distribution was not significant (p = 0.259). For TNF-α-308G/A, individuals with both GA and AA genotypes had lower ORs when compared with the GG genotype, implying the A allele could confer protection against Toxoplasma ocular lesions. CONCLUSIONS: IFN-γ +874T allele may increase the risk of ocular lesions in Toxoplasma infection. The principle of natural selection seems to also play a role. The less common TNF-308A allelic form could be protective against the development of Toxoplasma ocular infection.

Molecular and pathogenic effects of endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 in MHC-I-associated inflammatory disorders: Towards a unifying view.

The inflammatory diseases that are most strongly associated with major histocompatibility Complex class I (MHC-I) alleles are also influenced by endoplasmic reticulum aminopeptidase (ERAP) 1 and/or 2, often in epistasis with the susceptibility MHC-I allele. This review will focus on the four major MHC-I-associated inflammatory disorders: ankylosing spondylitis, birdshot chorioretinopathy, Behçet's disease and psoriasis. The genetics of ERAP1/ERAP2 association and the alterations induced by polymorphism of these enzymes on the risk MHC-I allotypes will be examined. A pattern emerges of analogous effects on peptide length, sequence and affinity of disparate peptidomes, suggesting that similar peptide-mediated mechanisms underlie the pathogenesis and the joint contribution of ERAP1/ERAP2 and MHC-I to distinct inflammatory diseases. Processing of specific antigens, peptide-dependent changes in global properties of the MHC-I molecules, such as folding and stability, or both may be pathogenic.

Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen.

Birdshot chorioretinopathy is a rare ocular inflammation whose genetic association with HLA-A*29:02 is the highest between a disease and a major histocompatibility complex (MHC) molecule. It belongs to a group of MHC-I-associated inflammatory disorders, also including ankylosing spondylitis, psoriasis, and Behçet's disease, for which endoplasmic reticulum aminopeptidases (ERAP) 1 and/or 2 have been identified as genetic risk factors. Since both enzymes are involved in the processing of MHC-I ligands, it seems reasonable that common peptide-mediated mechanisms may underlie the pathogenesis of these diseases. In this study, comparative immunopeptidomics was used to characterize >5000 A*29:02 ligands and quantify the effects of ERAP1 polymorphism and expression on the A*29:02 peptidome in human cells. The peptides predominant in an active ERAP1 context showed a higher frequency of nonamers and bulkier amino acid side chains at multiple positions, compared with the peptides predominant in a less active ERAP1 background. Thus, ERAP1 polymorphism has a large influence, shaping the A*29:02 peptidome through length-dependent and length-independent effects. These changes resulted in increased affinity and hydrophobicity of A*29:02 ligands in an active ERAP1 context. The results reveal the nature of the functional interaction between A*29:02 and ERAP1 and suggest that this enzyme may affect the susceptibility to birdshot chorioretinopathy by altering the A*29:02 peptidome. The complexity of these alterations is such that not only peptide presentation but also other potentially pathogenic features could be affected.

The immunopathogenesis of birdshot chorioretinopathy; a bird of many feathers.

Birdshot chorioretinopathy (BSCR) is a bilateral chronic intraocular inflammation or posterior uveitis that preferentially affects middle-aged Caucasians. BSCR is characterized by distinctive multiple choroidal hypopigmented lesions in combination with retinal vasculitis and vitritis, and the extraordinary feature that virtually all patients are HLA-A29 positive. Its pathophysiology is still poorly understood. BSCR is the strongest documented association between HLA and disease in humans, which makes it an excellent model for studying the underlying immuno-genetic mechanisms of HLA class I-associated diseases. Although the association with HLA-A29 suggests that it is directly involved in the presentation of peptide antigens to T cells, the exact contribution of HLA-A29 to the pathophysiology of BSCR remains enigmatic. This article revisits the HLA-A29 peptidome using insights from recent studies and discusses why HLA-A29 can be considered a canonical antigen presenting molecule. The first genome-wide association study facilitated novel concepts into a disease mechanism beyond HLA-A29 that includes strong genetic predisposition for the ERAP2 gene that affects antigen processing for HLA class I. Furthermore, patients manifest with pro-inflammatory cytokine profiles and pathogenic T cell subsets that are associated with IL-17-linked inflammation. We are beginning to understand that the underlying biology of BSCR comprises various pathologic aspects branched into multiple molecular pathways. We propose to employ Systems Medicine to reveal their dynamic interplay for a holistic view of the immunopathology of this intriguing archetypal HLA class I-associated disease.

A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

Interleukin-6 gene polymorphism (-174 G/C) is associated with toxoplasmic retinochoroiditis.

PURPOSE: Experimental data have demonstrated a relevant role for IL-6 in the modulation of acute ocular toxoplasmosis. Therefore, we aim to investigate the possible association between the IL-6 gene polymorphism at position -174 and toxoplasmic retinochoroiditis (TR) in humans. METHODS: Ninety-seven patients with diagnosed TR were recruited from the Uveitis Section, Federal University of Minas Gerais. For comparison, 83 healthy blood donors with positive serology for toxoplasmosis and without retinal signs of previous TR were included in the study. Genomic DNA was obtained from oral swabs of individuals and amplified using polymerase chain reaction (PCR) with specific primers flanking the locus -174 of IL-6 (-174G/C). PCR products were submitted to restriction endonuclease digestion and analysed by polyacrylamide gel electrophoresis to distinguish allele G and C of the IL-6 gene, allowing the detection of the polymorphism and determination of genotypes. RESULTS: There was a significant difference in the genotype (χ(2) = 12.9, p = 0.001) and allele (χ(2) = 6.62, p = 0.01) distribution between TR patients and control subjects. In a subgroup analysis, there was no significant difference in genotypes and allele frequencies regarding TR recurrence. CONCLUSIONS: This study suggests that the genotypes related with a lower production of IL-6 may be associated with the occurrence of TR.

Granulomatous keratic precipitates in birdshot retinochoroiditis.

With the purpose of facilitating clinical studies of this infrequent disease, an expert panel published research criteria for birdshot retinochoroiditis (RCBRC). The aim of our study was to investigate the sensitivity of the exclusion criteria of the RCBRC as applied to all patients seen in our center with a diagnosis of BRC. This was a single center retrospective study involving all patients with an ocular inflammatory disease seen at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, between 1995 and 2012. The percentage of patients with a diagnosis of BRC was identified. The exclusion criteria of the RCBRC were applied to all patients and the percentage of patients with absence of keratic precipitates (KPs) and absence of posterior synechiae were calculated. Out of 1,504 new patients, 25 patients (1.66 %; 19 female, 6 male) were diagnosed with BRC and 19 patients had sufficient data to be included in the study (1.26 %, 13 female). All patients were positive for HLA-A29 testing. The sensitivity of the RCBRC with respect to the exclusion criteria applied to our patient cohort was 84.2 % due to the exclusion of three patients showing KPs. Our study supports the motion to re-evaluate the RCBRC, since granulomatous KPs can be present and are more frequent than previously estimated and stringent application of the criteria would lead to a substantial loss of study patients.

Interleukin-17 production and T helper 17 cells in peripheral blood mononuclear cells in response to ocular lysate in patients with birdshot chorioretinopathy.

PURPOSE: To determine the cytokine response to ocular lysates of peripheral blood mononuclear cells (PBMCs) from patients with birdshot chorioretinopathy (BSCR). METHODS: In the PBMCs of 19 patients with BSCR, T cell cytokine production in response to human retina and choroid lysates was analyzed with flow cytometry and compared to the responses against skin lysates. Five patients had active disease and had not yet been treated (naïve to systemic therapy); 14 patients had either immunomodulatory therapy (IMT) or inactive disease (referred as inactive/IMT). The PBMCs of 11 HLA-A29-positive healthy individuals were used as controls. RESULTS: The levels of interleukin-17 (IL-17) in supernatant of cultures stimulated with retina lysate were higher in patients with active BSCR compared to the HLA-A29 positive controls. The levels of other T cell cytokines (IL-10 and interferon-γ [IFN-γ]) in PBMC cultures did not change significantly after stimulation with ocular lysate. The frequency of CD4(+) IL-17(+) (T helper 17 [Th17]) T cells but not of CD4(+) IFN-γ (Th1) T cells was elevated in the PBMCs of patients with active BSCR stimulated by retina lysates compared to skin lysates. CONCLUSIONS: Our data demonstrate that PBMCs exhibit an IL-17-mediated immune response to retina lysate in patients with active disease naïve to systemic therapy. This is accompanied by the enrichment of IL-17-producing CD4(+) T cells. These findings support the current concept of chronic Th17-cell mediated inflammation and provide evidence that links the Th17 signatures to ocular-specific immune responses in BSCR.

Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis / Polimorfismo genético para IFNγ +874T/A em pacientes com toxoplasmose aguda

INTRODUCTION: A single nucleotide polymorphism (SNP) in the gene encoding gamma interferon influences its production and is associated with severity of infectious diseases. This study aimed to evaluate the association of IFNγ+874T/A SNP with duration of disease, morbidity, and development of retinochoroiditis in acute toxoplasmosis. METHODS: A case-control study was conducted among 30 patients and 90 controls. RESULTS: Although statistical associations were not confirmed, A-allele was more common among retinochoroiditis cases and prolonged illness, while T-allele was more frequent in severe disease. CONCLUSIONS: Despite few cases, the results could indicate a relation between IFNγ+874T/A single nucleotide polymorphism and clinical manifestations of toxoplasmosis.

INTRODUÇÃO: Um polimorfismo de nucleotideo único (SNP) no gene codificante para interferon gama influencia a sua produção e pode estar associado à gravidade de diversas doenças infecciosas. O objetivo deste estudo foi avaliar a associação entre SNP para IFNγ+874T/A com a duração da doença, a morbidade e o desenvolvimento de retinocoroidite na toxoplasmose aguda. MÉTODOS: Estudo de caso-controle incluindo 30 pacientes e 90 controles. RESULTADOS: Apesar da ausência de associação estatística, o alelo A foi mais comum entre os casos com retinocoroidite e doença prolongada e o alelo T nas formas mais severas. CONCLUSÕES: Os dados encontrados sugerem uma relação entre o polimorfismo de base única em IFNγ+874T/A com a morbidade e com o desenvolvimento de retinocoroidite por toxoplasmose.

Susceptibility to toxoplasmic retinochoroiditis is associated with HLA alleles reported to be implicated with rapid progression to AIDS.

BACKGROUND/AIMS: The frequency of HLA markers associated with rapid progression to AIDS was evaluated in Brazilian patients with AIDS exhibiting or not toxoplasmic retinochoroiditis (TRC). METHODS: 98 AIDS patients (25 with TRC, 43 with anti-T. gondii antibodies but without TCR, and 30 without anti-T. gondii antibodies and without TCR) were studied. RESULTS: The HLA-B35 was significantly increased in TRC group (p=0.0038). CONCLUSION: The presence of HLA-B35 may simultaneously predispose to progression to AIDS and TRC.

[Ocular signs of a mitochondrial trifunctional protein defect. A long-term follow-up]. / Okuläre Zeichen eines mitochondrialen trifunktionalen Proteindefekts. Eine Langzeitbeobachtung.

A 13-year-old boy presented with a defect of the mitochondrial trifunctional protein (MTP). The MTP complex catalyses ß-oxidation of long chain fatty acids. Disorders of this multienzyme complex result in accumulation of hydroxylated long chain fatty acids which leads to chorioretinopathy. Ophthalmoscopic findings in these patients include fine hyperpigmentation while autofluorescence reveals hyperfluorescent granules at the posterior pole. Visual acuity, visual fields and electroretinography are within the normal range. A special long chain fatty acid-reduced diet seems to delay the progression of chorioretinopathy.

Genetic polymorphism for IFNγ +874T/A in patients with acute toxoplasmosis.

INTRODUCTION: A single nucleotide polymorphism (SNP) in the gene encoding gamma interferon influences its production and is associated with severity of infectious diseases. This study aimed to evaluate the association of IFNγ+874T/A SNP with duration of disease, morbidity, and development of retinochoroiditis in acute toxoplasmosis. METHODS: A case-control study was conducted among 30 patients and 90 controls. RESULTS: Although statistical associations were not confirmed, A-allele was more common among retinochoroiditis cases and prolonged illness, while T-allele was more frequent in severe disease. CONCLUSIONS: Despite few cases, the results could indicate a relation between IFNγ+874T/A single nucleotide polymorphism and clinical manifestations of toxoplasmosis.

HLA-A29 and birdshot chorioretinopathy.

Birdshot chorioretinopathy primarily affects patients of European descent. At least 96%, if not all patients, are HLA-A29 carriers. HLA-A*29:01 and HLA-A*29:02, the two main subtypes of HLA-A29, differ only by a single mutation. In the general population HLA-A*29:02 is most frequent in whites, while HLA-A*29:01 is more frequent in Asians. The differential distribution of HLA-A*29:01 and HLA-A*29:02 has been actively debated as an explanation for the selective development of the disease in patients of European descent, but is no longer a valid argument. Another factor, probably not HLA linked, is either protective in Asians and in Africans or, conversely, triggers an autoimmune reactivity that is possibly present in whites and absent in Asians and in Africans. HLA-A*29:02 transgenic mice in which a spontaneous posterior uveitis is observed after 6 months of age provide further evidence that the HLA-A29 molecule plays a role in the pathogenesis of the disease.