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IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses, trimming peptides and loading onto HLA class I molecules. Coding single nucleotide polymorphisms within ERAP1 are associated with autoimmune diseases, viral infections, and cancer development. Our purpose was to analyze the influence of ERAP1 variants on fibrogenesis in hepatitis C virus (HCV)–infected patients. A range of ERAP1 polymorphisms were genotyped in 722 unrelated Caucasian patients diagnosed with chronic HCV from two Spanish cohorts. Patients were classified according to their fibrosis stage. Paraffin-embedded tissue microarrays were constructed to assess ERAP1 expression (HCV = 38; alcoholic = 20) by immunohistochemistry. A statistical algorithm was applied to derive a fibrogenesis prediction model. The ERAP1 variants rs30187/T (K528, pc

Objective The killer cell immunoglobulin-like receptors (KIRs) form a group of regulatory molecules that specifically recognize HLA class I molecules. The aim of this study was to analyze the possible contribution of the KIR3DL1 and KIR3DS1 alleles, in addition to HLA–B27, in the susceptibility to ankylosing spondylitis (AS) in a population of individuals from Spain. Methods We genotyped the KIR3DS1 and KIR3DL1 alleles in 2 cohorts of patients with AS and healthy control subjects. In total, 270 patients with AS and 435 healthy, HLA–B27–positive matched control subjects from Spain were enrolled. The KIR3DS1 and KIR3DL1 alleles were genotyped by sequence-specific oligonucleotide probe–polymerase chain reaction, and their association with AS was analyzed. All individuals were typed for HLA–B. Results The KIR3DS1*013 allele was solely responsible for the increased frequency of the activator receptor KIR3DS1 in patients with AS compared with healthy HLA–B27–positive control subjects (35.7% versus 22.6% [P = 10−6], odds ratio 1.90, 95% confidence interval 1.50–2.40). The increased frequency of the KIR3DS1*013 allele in patients with AS was independent of the presence or absence of the HLA–Bw4I80 epitope. Moreover, the null allele KIR3DL1*004 was a unique inhibitory KIR3DL1 allele that showed a negative association with AS in the presence of HLA–Bw4I80. Conclusion The increased frequency of the KIR3DS1*013 allele in patients with AS is clearly independent of the presence of the HLA–Bw4I80 epitope, whereas the presence of inhibitory allotypes such as KIR3DL1*004 demonstrated a negative association in patients with AS in the presence of HLA–Bw4I80. As a consequence, the influence of KIR genotypes on AS susceptibility would be mediated by a general imbalance between protective/inhibitory and risk/activating allotypes.

The role of MICA antibodies in acute heart allograft rejection was examined utilizing 190 pre- and post-transplant serum samples from 44 patients collected during the first year after transplantation. MICA antibodies were detected by CDC test on recombinant cell lines and by the newly developed Luminex MICA antibody detection assay. Additionally, MICA expression was analyzed by 'real time' RT-PCR and by immunohistochemistry in 10 endomyocardial biopsies. Only two subjects had HLA antibodies post-transplant. Nevertheless, MICA antibodies were found in a significant number of subjects. The prevalence of MICA antibodies was significantly higher among those with severe acute rejection (AR) than in those without rejection (60.7% vs. 14.3%, p = 0.0038 by CDC; 55.5% vs. 5.7%, p = 0.0020 by Luminex). In most cases, the appearance of MICA antibodies post-transplant precedes AR. Following transplantation, MICA up-regulation correlated with histological evidence of severe rejection. Monitoring for MICA antibodies post-transplant may be useful to establish new risk factors for acute rejection.

It is well known that certain HLA class II alleles confer an increased risk for developing multiple sclerosis (MS). Recent studies have suggested HLA class I as a region that may also contribute to the development of MS. In this study, we investigated the association between HLA-DR, HLA-B alleles, and major histocompatibility complex (MHC) class I-chain-related gene A (MICA) transmembrane (MICA-TM) polymorphisms and disease progression in 104 MS patients and 116 healthy controls. DR1 was found to be decreased in patients when compared with controls (p(c) = 0.012). Neither HLA-B nor HLA-DR alleles were found to be associated with MS susceptibility. Furthermore, the prevalence of MICA-A5 in patients with relapsing MS was 9% while the prevalence in progressive forms was 42% (p(c) = 0.0015). The extended haplotypes related to MICA-TM5 that were found in our population were DR7-MICA5-B64 (EH 64.1, delta(s) = 0.38), DR4-MICA5-B62 (EH 62.1, delta(s) = 0.28), and DR11-MICA5-B35 (EH35.1, delta(s) = 0.10), but none of them were found to be associated to MS susceptibility or disease progression. Our data could indicate a possible role of MICA-TM in MS prognosis.

The possibility that susceptibility to celiac disease (CD) might be influenced by the MHC class I chain-related gene family, MICA and MICB, has been previously reported. In this study, we analyzed the MICB promoter and examined the association of the polymorphisms found within such in a group of CD patients. To study the MICB promoter we sequenced the 5′ flanking region of MICB gene in DNA from homozygous B-lymphoblastoid cell lines corresponding to the most frequent MICB alleles found in our population (MICB*00502, MICB*002, MICB*004, and MICB*008). DNA from a MICB*003 homozygous individual was also analyzed. Sequence analysis revealed six single nucleotide polymorphisms located at positions 45860 C/A, 45862 G/C, 45877 C/G, 46113 A/C, 46219 G/C, and 46286 G/C and an insertion of 2 bp --/AG at position 45944 according to the published genomic sequence. Those polymorphisms were found to be associated in four different haplotypes corresponding to different MICB alleles. Subsequently, 126 CD subjects and 117 healthy controls were typed by polymerase chain reaction using sequence-specific primers for these polymorphisms. MICB promoter polymorphism haplotypes were also found in our population and showed strong linkage disequilibrium with MICB alleles. MICB promoter polymorphism Haplotype 3, included in MICB*002 and MICB*008 alleles, was found to be overrepresented in CD patients (79.4% CD patients vs 45.3% healthy controls; pc < 0.0001; OR = 4.64; CI 95% = 2.64–8.16). Both MICB*008 and MICB*002 alleles were found as part of the CD susceptibility extended haplotypes B8/DR3/DQ2, B18/DR3/DQ2, and DR4/DQ8.

The HLA-Cw*0602 has been associated with psoriasis in different ethnic groups. But, it remains unclear whether HLA-C is the PSORS1 gene (the psoriasis gene in the MHC). Thus, several case-control studies have been performed in order to investigate whether HLA-C itself determines the susceptibility to the disease. We studied 59 Jewish patients with type I psoriasis and 79 matched controls. Polymorphic genes and markers from HLA-B (centromeric to HLA-C) to the corneodesmosin (CDSN) gene (telomeric to HLA-C) were genotyped in order to determine their contribution to the susceptibility to psoriasis. Neither HLA-Cw*0602 nor the allele CDSN*TTC were significantly associated with psoriasis with the size of the sample studied. The genes and markers telomeric to HLA-C such as the microsatellite C1_4_4 (OR = 2.6, 95% CI = 1.4-4.7, p(c) = 0.018) the octamer transcription factor (OTF)-3 gene (OR = 2.6, 95% CI = 1.6-4.3, p(c) = 0.0001) and the alpha-helix coiled-coil rod homologue (HCR) gene (OR = 2.5, 95% CI = 1.3-4.5, p(c) = 0.004), however, were associated with the disease. These results suggest that a major psoriasis susceptibility gene is likely to be located within a region of 150 kb telomeric to HLA-C and centromeric to the CDSN gene.

Objective To analyze the HLA distribution in a population of individuals from Zambia in order to establish a possible relationship between the progression of human immunodeficiency virus (HIV) infection and the development of spondylarthropathy (SpA). Methods A large epidemiologic analysis of rheumatology patients living in Zambia was performed in order to identify those who had SpA. We selected 64 patients with SpA and found that 54 also had HIV type 1 (HIV-1) infection; only 10 were HIV negative. Additionally, we selected 57 HIV-infected individuals without SpA and 43 healthy controls. Among all of the HIV-1–infected patients, 25 SpA-positive and 24 SpA-negative patients were classified as slow progressors to acquired immunodeficiency syndrome (AIDS), and 8 SpA-positive and 26 SpA-negative patients were classified as rapid progressors. All patients were typed for HLA–B alleles. Results Of the 64 patients with SpA, HIV infection was observed in 54 (84%). The frequency of B*5703 was increased in patients who were SpA positive and HIV positive compared with patients who were SpA negative and HIV positive (P = 0.0002, odds ratio [OR] 8.28). Among patients who were slow progressors to AIDS, this allele was overrepresented in those with SpA compared with those without SpA (corrected P = 0.001, OR 26.25). Conclusion HLA–B*5703 seems to be a protective allele against the progression of HIV infection but could influence the increased incidence of SpA observed in this population.

The aim of this study was to investigate the association of MHC genes in the development of celiac disease (CD) and its diverse clinical forms in a Saharawi population.One hundred and twenty-five CD patients and 98 healthy controls were selected from the Saharawi refugee camps in Tindouf. All were investigated for the presence of antitransglutaminase 2 antibodies. Patients were divided into two groups according to their clinical manifestations: 70 typical and 55 atypical. Patients and controls were typed for HLA-B, DRB1, DQB1, and DQA1, and for MICA transmembrane polymorphism.The frequency of HLA-DQ2 in Saharawi controls was notably increased compared with other populations. No differences in the distribution of DQ2 in either group of patients were found. However, the haplotype B8/DR3/DQ2 was notably overrepresented in atypical patients compared to typical ones (pc= 0.001). The MICA-A5.1 allele was increased in atypical CD patients compared to those with typical forms (pc= 0.0006). Finally, we found that the increased frequency of MICA-A5.1 in the atypical group was independent of the linkage disequilibrium with B8/DR3/DQ2 haplotype (p= 0.02).The elevated prevalence of CD in Saharawi seems to be related to the high frequency of HLA-DQ2 in this population. However, the development of atypical or typical forms of the disease may be due to a gene or genes located in the class I side of the haplotype B8/DR3/DQ2, especially MICA. This appears not to be implicated in the susceptibility to CD but may play an important role in the development of the different forms of the disease.

We have studied the polymorphism of HLA class I in two West African Pygmy populations, namely, the Bakola from Cameroon and the Mbenzele from the Central African Republic. A unique number of HLA alleles and haplotypes showed specific patterns of these populations. In this study, we identify two alleles (B*37, B*41) and three haplotypes (A*30-B*37, A*66-B*41 and A*68-B*58) that appear to be 'private' or typical of Western Pygmies. These data reflect similarities with the AKA Pygmies from the Central African Republic. On the other hand, we failed to identify alleles that are found at high frequencies among other sub-Saharan populations (B*42, B*51). Allelic and haplotypic frequency distributions show differences between the two Pygmy groups, e.g. B*35 was very common in the Mbenzele but has been found to be absent in the Bakola. In contrast, B*53, which is found in the Bakola, has been found to be rare in the Mbenzele Pygmies. In order to analyse the genetic relationships of the Bakola and Mbenzele Pygmies with other sub-Saharan populations, HLA gene frequencies were subjected to the Neighbour-Joining tree analysis. The Mbenzele, Bakola and AKA were found to be relatively close to each other and isolated from other sub-African populations. However, both the genetic distances and the within-group variation suggests that the Bakola are more admixed with Bantu farmers than Mbenzele.

Recent evidence from several studies has suggested a genetic predisposition in the pathogenesis of ulcerative colitis (UC), which is especially related with major histocompatibility complex (MHC) genes. The aim of this study was to investigate the possible association of human leukocyte antigen (HLA-B, HLA-DR) and MHC class I chain-related-transmembrane (MICA-TM) polymorphism with the behavior and extension of UC. We selected 121 unrelated patients with UC. These were divided into two groups according to the extension of the disease: 31 patients with distal UC and 90 with wide extension UC; 116 blood donors were also selected as healthy controls, all of whom were typed for HLA-B, HLA-DR, and MICA-TM alleles. HLA-B7 was found to be overrepresented in distal UC patients compared with those with extensive UC (p(c) = 0.007, OR = 5.33) and healthy controls (p(c) = 0.03, OR = 4.09). The MICA-A5.1 allele was also increased in distal UC (p(c) = 0.015, OR = 3.82) when compared with extensive forms. These alleles are in strong linkage disequilibrium in our population. The MICA-A5 allele was significantly increased in extensive forms when compared with healthy controls(p(c) = 0.02, OR = 2.4). According to our results, MICA-A5.1 allele seems to be protective against extensive forms of UC, and MICA-A5 may condition a worse progression of the disease. These results are in agreement with other studies that suggest a similar role of such alleles in other diseases, such as insulin-dependent diabetes mellitus and celiac disease.

Objective Tumor necrosis factor-α (TNF-α) plays a key role in the inflammatory response and pathogenesis of Crohn’s disease (CD). TNF-α −308A polymorphism within the TNF-α gene promoter has been associated with enhanced TNF-α production in vitro. The aim of this study was to investigate the effect of TNF-α promoter polymorphism at −308 on the susceptibility and phenotypic expression of fistulizing CD.

Objective To investigate the contribution of HLA class I alleles in the susceptibility to primary ankylosing spondylitis (AS) in West African patients living in Togo. Methods A large epidemiologic analysis of 9,065 West African rheumatology patients living in Togo was performed in order to identify those who had AS. Eight Togolese patients with AS were identified. HLA was typed by polymerase chain reaction using sequence-specific oligonucleotide probes. DNA typing was also performed on a control population of 85 healthy subjects matched for ethnic background. Results A significant association between AS and B*14 was identified. This allele was found in 62.5% of the AS patients (odds ratio 69), but was carried by only 2% of the healthy controls. Analysis for B14 subtypes showed that B*1403 was the predominant allele in AS patients (odds ratio 171), and that this allele was absent in healthy controls. B27 was virtually absent, being observed in only 1 AS patient (B*2705). Conclusion HLA–B*1403 shows the B27 “supertype” motif and may exert an effect on AS susceptibility according to the arthritogenic peptide model. The association of B*1403 with AS has not previously been reported in either population.

Background and aims: Coeliac disease (CD) is an enteropathic disorder characterised by a strong association with major histocompatibility complex (MHC) heterodimer HLA-DQ2. It has been suggested that other HLA class I genes in combination with DQ may also contribute to CD susceptibility. The aim of this study was to investigate whether other candidate genes modify the risk of developing different clinical forms of CD. Patients and methods: We studied 133 Spanish coeliac patients, divided according to their clinical presentation into typical and atypical groups, and 116 healthy controls. All were typed by polymerase chain reaction-sequence specific primers (PCR-SSP) at HLA-B, DRB1, DQA1, and DQB1 loci and for exon 5 of the MHC class I chain related gene A (MICA). Results: No differences were found in the frequency of the DQA1*0501/DQB1*0201 heterodimer in either group. The risk of typical CD was significantly associated with the DR7/DQ2 haplotype (pc=0.02, odds ratio (OR)=3.4, ethiological fraction (EF)=0.4). Extended haplotype (EH) 8.1 (B8/DR3/DQ2) was found to be overrepresented in the atypical form compared with the typical form (pc=0.001, OR=4.19, EF=0.56). The trinucleotide repeat polymorphism MICA-A5.1 was found to be increased in the atypical group of patients compared with the typical group (pc=0.00006, OR=8.63, EF=0.81). This association was independent of linkage disequilibrium with EH8.1 as this was also found to be increased in EH8.1 negative atypical patients compared with the typical group (pc=0.004, OR=6.66, EF=0.56). Conclusions: Our results showed that the risk of developing typical forms of CD was associated with DR7/DQ2 haplotype, and the presence of B8/DR3/DQ2 was significantly increased in atypical patients. In these, the MICA-A5.1 allele confers an additive effect to the DR3/DQ2 haplotype that may modulate the development of CD.

HLA-B27 is the strongest HLA molecule associated with a disease. However, the reason only a small fraction of HLA-B27 positive individuals develop spondyloarthropathies is still unknown. Recent advances in genetics support the fact that additional genetic factors influence the disease and that the environmental factors may be ubiquitous. The mechanism of association of HLA-B27 and disease remains unknown, but recent studies reveal some peculiar properties of accessory molecules in antigen presentation of B27. Furthermore, research has focused on the analysis of HLA-B27-restricted processing and presentation of a bacteria-derived peptide as playing a key role in the development of spondyloarthropathy. Other studies support a more complex interaction between bacteria and HLA-B27 and suggest that other roles unrelated to antigen presentation might contribute to the development of SpA.

To investigate the relative contribution of HLA antigens in the susceptibility to psoriasis and to localize additional genetic factors involved in psoriatic arthritis (PsA).DNA from 45 patients with psoriasis, 65 with PsA, and 177 healthy control subjects was examined by polymerase chain reaction (PCR) using sequence-specific oligonucleotide probes to determine HLA-C. To examine whether MICA (class I major histocompatibility complex chain-related gene A) confers additional susceptibility, trinucleotide repeat polymorphism in the transmembrane region of the MICA gene was investigated by radioactive PCR. Further analysis of MICA was made by PCR-single-strand conformational polymorphism to determine the allelic variant corresponding to MICA transmembrane polymorphism.Our results reveal new findings: 1) the frequency of the Cw*0602 allele was significantly increased in both patient groups: psoriasis (corrected P [Pcorr]10(-5), relative risk [RR] 6.2), PsA (Pcorr10(-6), RR 6.3), 2) the trinucleotide repeat polymorphism MICA-A9 was present at a significantly higher frequency in PsA patients (Pcorr0.00035, RR 3.2), whereas a similar distribution was found in both the control and psoriasis population, 3) this polymorphism corresponds to the MICA-002 allele and was found to be overrepresented in patients with the polyarticular form (Pcorr0.0008, RR 9.35), 4) the increase in MICA-A9 in PsA patients is independent of linkage disequilibrium with Cw*0602, 5) this allele confers additional relative risk (RR 3.27, etiologic fraction 0.44; etiologic fraction is the proportion of disease cases among the total population that are attributable to 1 allele when the relative risk is1) in PsA patients who carry Cw*0602.The data obtained in this study are consistent with the polygenic inheritance of psoriasis. Cw*0602 appears to be the stronger genetic susceptibility factor for psoriasis. Independent of the HLA-C association, MICA-A9 polymorphism corresponding to the MICA-002 allele is a possible candidate gene for the development of PsA.

We have characterized HLA-B27 alleles in a sample of the population from the Azores (n=46) with the aim of investigating the contribution of different subtypes to ankylosing spondylitis (AS). The study was carried out using PCR-SSOP and in some samples genomic sequencing was conducted. Some significant new finding have arisen from this study. First, B*2705,B*2702,B*2703,B*2707 and B*2708 alleles were found to be represented in this population. The polymorphism of B27 alleles found in a sample of the population from the Azores is higher than the Caucasian groups described. B*2703 and B*2707 have not previously been described to be represented in Caucasians and this could indicate admixtures with different populations of the world. In addition, the B*2708 allele was found to be associated with AS in a large family from the Azores. This association has not been previously reported in either ethnic group and needs to be confirmed in other population studies. This is of considerable interest since has only been described as a rare subtype underrepresented in the British population and has not been previously found to be associated with AS. B*2708 carries the sequence specifying the Bw6 epitope in contrast to most B27 alleles which carry a Bw4 sequence. Differences in this region (residues 77-83) can alter the F-pocket and affect T-cell recognition. The importance that these molecular changes can play in the pathogenesis of AS is discussed.

We report that the allele MICB 0050204(1) allele, present in the majority of the Spanish population (70% of healthy controls) is characterized by the presence of an extra exon found between the sequence corresponding to exon 1 and 2. This is generated by a dinucleotide polymorphism in the first MICB intron that introduces a new splice junction, which can generate, by alternative splicing, transcripts with an additional exon. This new exon contains a premature stop codon and therefore the transcript does not produce a functional protein.

The aim of this study was to analyse the distribution of KIR haplotypes and the KIR2DL2/3 alleles in chronic HCV-infected patients in order to establish the influence on the response to pegylated interferon plus ribavirin classical treatment. The alleles study of previously associated KIR2DL2/3 showed that KIR2DL2*001 was more frequent in non-SVR (NSVR) (42.2% vs. 27.5%, p

With the aim of clarifying the role of several polymorphisms around the HLA-C locus in the clinical expression of PsA, the distribution of several polymorphic markers and genes located around the HLA-C locus was analyzed in a well-established cohort of 110 patients with PsA, 50 patients with psoriasis alone, and 110 healthy controls. The frequency of these genes was also analyzed by PsA articular models, based on three main subgroups: oligoarthritis, polyarthritis, and spondylitis. Distal interphalangeal joint (DIP) involvement was associated with the presence of MICB-CA20 (OR 6.0, 95% CI: 1.58–22.69, P=0.005). HLA-DRB*07 was associated with oligoarticular forms of PsA (OR 4.1, 95% CI: 1.8–9.3, P=0.0007). The spondylitic forms overexpressed the antigen HLA-B*27 (OR 5.7, 95% CI: 2.4–13.6, P=0.0001). MICA-A5.1 showed association with polyarthritis (OR 3.7, 95% CI: 1.5–8.8, P=0.006). Genes telomeric to HLA-C were overexpressed in psoriasis but not in PsA subphenotypes. This study shows that the region centromeric to HLA-C is a key region that expresses not only disease risk genes but also genes that help explain the phenotypic variability of PsA.

Autophagy is a highly conserved mechanism which is essential for the maintenance of cellular homeostasis in response to cellular stress. Autophagy has been conserved from yeast to humans as a quality control process that is involved in the recognition and turnover of damaged proteins and organelles. It is also a response mechanism to nutrient starvation. In mammals, autophagy is involved in antigen presentation, tolerance, inflammation and protection against neurodegenerative diseases. The decrease of autophagy during aging reduces the removal of damaged organelles and increases the accumulation of waste products in the cells. In this chapter, we review these aspects of autophagy along with their role in self-nonself distinction, their implication in innate and adaptive immune response, and its dysregulation in the pathology of certain inflammatory and autoimmune diseases.

Bacteriophages are probably the oldest viruses, having appeared early during bacterial evolution. Therefore, bacteria and bacteriophages have a long history of co-evolution in which bacteria have developed multiple resistance mechanisms against bacteriophages. These mechanisms, that are very diverse and are in constant evolution, allow the survival of the bacteria. Bacteriophages have adapted to bacterial defense systems, devised strategies to evade these anti-phage mechanisms and restored their infective capacity. In this chapter, we review the bacterial strategies that hinder the phage infection as well as the counter-defense mechanisms developed.

The Major Histocompatibility Complex (MHC) is a genomic region that contains genes that encode proteins involved with antigen presentation and, therefore, plays an important role in the adaptive immune system. The origin of these genes was probably an ancestral MHC that appeared before the emergence of the adaptive immune system and contained genes related to immunity. The organization of MHC genes varies in different groups of vertebrates; although, there are some characteristics that are maintained in all groups, which indicates that they confer some evolutionary advantage: Organization of the genes to form clusters and genetic polymorphisms. The study of how the MHC appeared during evolution and how it is organized in different species can help us clarify what features are essential in their participation in self-nonself recognition.

The Major Histocompatibility Complex (MHC) is a genomic region that contains genes that encode proteins involved with antigen presentation and, therefore, plays an important role in the adaptive immune system. The origin of these genes was probably an ancestral MHC that appeared before the emergence of the adaptive immune system and contained genes related to immunity. The organization of MHC genes varies in different groups of vertebrates; although, there are some characteristics that are maintained in all groups, which indicates that they confer some evolutionary advantage: Organization of the genes to form clusters and genetic polymorphisms. The study of how the MHC appeared during evolution and how it is organized in different species can help us clarify what features are essential in their participation in self-nonself recognition.

Autophagy is a highly conserved mechanism which is essential for the maintenance of cellular homeostasis in response to cellular stress. Autophagy has been conserved from yeast to humans as a quality control process that is involved in the recognition and turnover of damaged proteins and organelles. It is also a response mechanism to nutrient starvation. In mammals, autophagy is involved in antigen presentation, tolerance, inflammation and protection against neurodegenerative diseases. The decrease of autophagy during aging reduces the removal of damaged organelles and increases the accumulation of waste products in the cells. In this chapter, we review these aspects of autophagy along with their role in self-nonself distinction, their implication in innate and adaptive immune response, and its dysregulation in the pathology of certain inflammatory and autoimmune diseases.

The age of psoriasis onset has an important impact on the clinical expression and heritability of psoriasis. Psoriasis characteristics according to the age at disease onset have been extensively studied. However, the impact of the age of psoriasis onset on psoriatic arthritis (PsA) features has not been analysed in depth. The aim of the present paper is to analyse whether the age of psoriasis onset may have an impact on the clinical and genetic characteristics in a cohort of PsA patients.The study included 110 PsA patients classified in accordance with the CASPAR criteria. Patients were divided into early (onset age30 years) and late (onset age30 years) onset psoriasis, and clinical features were studied in accordance to this stratification. Distribution of several genes within the MHC region were analysed in accordance with the prior stratification, and their frequencies compared to that of 110 healthy matched blood donors.Compared to patients with late-onset disease, PsA patients with early-onset psoriasis showed more frequently: a longer psoriasis-arthritis latency period (9.9±6 years vs. 3.8±4 years, p=0.0001), a positive family history of disease (60.3% vs. 20.5%, OR 6.1, 95% CI: 2.5-15.0, p=0.0001), severe psoriasis (PASI 8.2±4 vs. 3.6±2.2, p=0.0001), clinical enthesitis (37.7% vs. 22.4%, OR 2.09, 95% CI: 0.9-4.9, p=0.08), and oligoarthritis (47.5% vs. 28.6%, OR 2.26, 95% CI: 1.02-5.02, p=0.04). MICA-A9 was associated with susceptibility in both early-onset (60.7% vs. 30%, p=0.0002) and late-onset patients (59.2% vs. 30%, p=0.0008). However, HLA-Cw*0602 was significantly increased in patients with early-onset psoriasis (73.8% vs. 17%, p0.0001), whereas the allele 384 of the microsatellite C1_4_4, located 34 kb telomeric to HLA-C locus, was increased only in late-onset cases (49% vs. 21%, p=0.001).Clinical and genetic features of PsA may differ depending on the age at psoriasis onset. This type of stratification should be considered in future genetic and epidemiological studies of PsA.

Joint Bone Spine - In Press.Proof corrected by the author Available online since vendredi 6 mai 2011

Killer immunoglobulin-like receptors (KIRs) are related to the activation and inhibition of NK cells and may play an important role in the innate response against infection with viruses such as hepatitis C virus (HCV). We examined whether the different combinations of KIRs with their HLA class I ligands influenced the response to combined treatment (pegylated alpha interferon and ribavirin) of patients infected by HCV. A total of 186 consecutive patients diagnosed with chronic HCV infection were analyzed. Seventy-seven patients exhibited HCV RNA levels at 6 months posttreatment and were called nonresponders (NR), while 109 cleared viral RNA and were named sustained viral responders (SVR). Patients were typed for HLA-B, HLA-Cw, KIR genes, and HCV genotype. In our study, the frequency of the KIR2DL2 allele was significantly increased in NR (P< 0.001; odds ratio [OR] = 1.95), as was the frequency of the KIR2DL2/KIR2DL2 genotype (P< 0.005; OR = 2.52). In contrast, the frequencies of the KIR2DL3 genotype (P< 0.001) and KIR2DL3/KIR2DL3 genotype (P< 0.05; OR = 0.54) were significantly increased in the SVR. Different combinations of KIR2DL2 and KIR2DL3 alleles with their ligands were analyzed. The frequency of the KIR2DL2/KIR2DL2-HLA-C1C2 genotype was significantly increased in the NR (P< 0.01; OR = 3.15). Additionally, we found a higher frequency of the KIR2DL3/KIR2DL3-HLA-C1C1 genotype in the SVR group (P< 0.05; OR = 0.33). These results were not affected by the HCV genotype. In conclusion, patients who carried the KIR2DL2/KIR2DL2-HLA-C1C2 genotype were less prone to respond to treatment. However, the KIR2DL3/KIR2DL3-HLA-C1C1 genotype clearly correlated with a satisfactory response to treatment, defined by the clearance of HCV RNA.

It has been widely reported that the major histocompatibility complex (MHC) class II region provides the main genetic contribution to multiple sclerosis (MS) susceptibility. However, recent studies have suggested that the MHC class I region may also contribute to the development of MS. In this study, we investigated the possible association of the human leukocyte antigen (HLA)-B, MHC class I chain-related gene B (MICB) and MHC class I chain-related gene A (MICA) genes, located in the MHC class I region, with MS susceptibility. For this purpose, we analyzed the distribution of HLA-DR, HLA-B, MICB and MICA alleles in 121 MS patients and 156 healthy controls. Neither HLA-B nor MICA alleles were found to be associated with MS susceptibility, and only the frequency of HLA-DRB1*01 allele was found to be increased in controls (31% vs 14%, P(c) = 0.011). However, MICB*004 allele frequency was significantly increased in MS patients (46.3% vs 23.3%, P(c) < 0.001, odds ratio = 2.82, 95% confidence interval = 1.68-4.73). Although, MICB*004 and HLA-DRB1*15 belong to the AH 7.1 ancestral haplotype, the association of MICB*004 to MS susceptibility was found to be independent of HLA-DRB1*15 in our population. This and previous studies clearly suggest that the MHC class I, in addition to class II, could be involved in MS susceptibility.

Killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) loci are both highly polymorphic. The aim of this study was to perform a KIR genotype analysis and examine, in concert with HLA-B27 genotypes, their influence on ankylosing spondylitis (AS) susceptibility in two Asian populations (one from China, 42 patients and 30 controls, and another from Thailand, 30 patients and 16 controls). In the Chinese population, we observed an increase of KIR3DS1, KIR2DS5, and KIR2DL5 gene frequencies in AS patients (p(c)0.005, p(c)0.001, and p(c)0.01, respectively). A similar increase was reported in the Thai population: KIR3DS1, KIR2DS5, and KIR2DL5 gene frequencies were higher in AS (p(c)0.05, p0.05, and p(c)0.05, respectively). Upon analyzing the KIR3DL1/3DS1 genotypes, we determined significant differences in both populations. The frequency of 3DL1/3DL1 was decreased in AS (p(c)0.005 and p(c)0.05 in the Chinese and Thai populations, respectively), whereas 3DL1/3DS1 demonstrated an increased frequency in AS (p(c)0.005 in the Chinese population and p(c)0.05 in the Thai population).

Recent studies demonstrated that dysregulation of NKG2D and its ligands, leading to activation of autoreactive effector cells, can trigger autoimmune diseases, but soluble forms of these ligands can downmodulate NKG2D expression in T effector cells. We investigated the presence of soluble major histocompatibility complex class I chain-related A or B (MICA or MICB) molecules in sera of multiple sclerosis (MS) patients and whether they play a role in the progression of the disease. Although soluble MICA serum levels did not differ, soluble MICB serum levels were higher in MS patients compared with controls. Moreover, the highest MICB levels were in MS patients during relapses. Using immunohistochemistry techniques, it was possible to locate MIC expression in neurons of MS demyelinating plaques that were intracellularly accumulated. Elevated soluble MICB levels exist in serum of multiple sclerosis patients related with disease activity. This may contribute to the modulation of immune response activity during relapses.

HLA-B27 confers susceptibility to ankylosing spondylitis (AS) but the mechanism linking this association remains unknown. Other properties unrelated to its natural role of antigen presenting function may be important in disease pathogenesis. We determined here the impact of N97D substitution on the folding and expression of HLA-B*2704 transfected in the 721.221 cell line. The mutation at position 97 abolishes the surface expression of non-conformational (HC10) and conformational (ME1) forms. The expression of ME1 forms was found to be absent in B*2704 N97D by immunoprecipitation and flow cytometry of fixed and permeabilized cell experiments with the conformation-sensitive ME1 antibody. However, immunoblotting cell lysates with HC10 revealed the presence of unfolded heavy chain (HC) and HC-dimer forms. The impact of the N97D mutation in the exit from the endoplasmic reticulum (ER) was analysed by western blot after endoglycosidase-H treatment, and it was found that B*2704 N97D was retained and accumulated as unfolded molecules. We tested for mutant association with transporter associated with antigen processing (TAP), calnexin (CNX), calreticulin (CLR) and beta2 microglobulin (beta2m). The wild-type B*2704 and N97D mutants were associated with TAP, CNX and CLR, although HC10 forms of mutant N97D interact more weakly with TAP. Only folded molecules of HLA-B*2704 were associated with beta2m. Surprisingly, the peptide-binding assay demonstrated the ability of unfolded N97D molecules to bind high-affinity peptides. It has been suggested that AS may arise because of aberrant folding of HLA-B27 molecules within the ER. Future work must therefore aim to clarify the functional connection between the unfolded protein response pathway in response to the accumulation of HLA-B27 in the ER. This mutant could be useful as a model for the misfolding of HLA-B27.

KIR and HLA loci are both highly polymorphic, and some HLA class 1 products bind and trigger cell-surface receptors specified by KIR genes. We examined whether KIR genes act in concert with HLA-B locus to control HIV-1 infection in a sample of Zambian patients. DNA samples from 88 Zambian patients with HIV-1 were examined. Patients were classified as either slow progressors (SP; n = 54) or rapid progressors (RP; n = 34) to AIDS. All were typed for HLA-B and KIR genes. Our results reveal an association between B*57 supertype (B*57s, which includes B*57 and B*58 alleles) and delayed progression to AIDS (p = 0.0007 by pc = 0.015; OR = 5.25). We also observed an increase incidence of Bw4-I80 in patients with slow progression (p = 0.001 by pc = 0.003, OR = 5). This increase was found to be secondary to B*57s. The presence of both KIR3DL1 and B*57S has a significant effect on progression to AIDS (p = 0.0008; OR = 5.61). B*57s genotypes with another HLA-B allele different from those in the trans position, which also had a specificity different to Bw4-I80 (Bw4-T80 or Bw6), was also greater in the SP than in the RP group (p = 0.00003; OR = 10.11). The presence of the inhibitory allele KIR3DL1 in combination with the HLA-B*57s alleles that contain the Bw4-I80 epitope, has a highly protective effect against progression to AIDS in Zambian patients.

The aim of the present study was to investigate, in 152 Spanish patients infected with hepatitis C virus (HCV), the possibility that killer cell immunoglobulin-like receptors (KIRs) influence progression to hepatocellular carcinoma. KIRs are related to the activation and inhibition of natural killer cells and may play an important role in the innate response against infection with such viruses as HCV. We found that the human leukocyte antigen-Bw4I80 epitope and the KIR3DS1 gene were more frequent in HCV carriers than in patients with hepatocellular carcinoma. Moreover, these associations were not independent of each other--the KIR3DS1/Bw4I80 genotype clearly was also more frequent in HCV carriers (odds ratio, 24.22).

BACKGROUND AND AIMS Celiac disease (CD) is an enteropathic disorder characterized by strong association with HLA-DQ2. Our aim was to investigate whether MICB, a gene located in the MHC class I region, may contribute to CD susceptibility. PATIENTS AND METHODS Total of 133 CD patients, previously reported to be associated with MICA-A5.1, and 116 controls were initially analyzed. Twenty-eight additional DQ2-negative CD patients were also studied. MICB was typed by PCR using sequence-specific primers. HLA-B, -DRB1, -DQA1, -DQB1, and MICA were also typed. RESULTS The allele MICB0106 was strongly associated with CD (pc < 0.000001, odds ratio (OR) = 5.6, 95% confidence interval (CI) = 3.1-10.1) and it was overrepresented in atypical patients compared with typical ones (pc = 0.04, OR = 2.9, CI = 1.4-6.1). MICB0106 was part of DR3-DQ2 haplotype (B8-MICA-A5.1-MICB0106-DR3-DQ2), and consequently a strong linkage disequilibrium between MICB0106 with DQ2 (lambdas = 1) and MICA-A5.1 (lambdas = 0.55) was found. To analyze whether the association of MICB is independent of this haplotype, its association was also studied in DQ2-negative patients (n = 46). DQ8 (28%vs 9%, p = 0.0085, pc = NS) and MICB0104 (52%vs 30%, p = 0.01, pc = NS) were increased in DQ2-negative patients. MICA-A5.1 was significantly increased in atypical patients (p(c)= 0.001, OR = 6.4, CI = 2.2-18.4), and this association was independent of DQ2 and DQ8 (pc = 0.02, OR = 2.6, CI = 1.1-6.1). CONCLUSIONS The expression of MIC genes on enterocytes under stressful conditions and their function as ligands of intraepithelial gammadelta and CD8 T cells, together with the data presented here suggest a potential role of MIC genes in the pathogenesis of CD.

Objective. To map the locus for susceptibility to psoriasis in patients with psoriatic arthritis. Methods. Seventy-four patients with psoriatic arthritis and 95 patients with psoriasis vulgaris were included in this study. Polymorphic genes and microsatellite markers centromeric (C1―2―5) and telomeric (C1―4―4, OTF3, HCR and the corneodesmosin gene) to HLA-C were studied in an association analysis. Typing was also performed on a control population of 104 matched donors. Results. The allele Cw*0602 was associated both with psoriasis [49 vs 21%, P c < 0.0003; odds ratio (OR) = 3.6, aetiological factor (AF) = 0.72] and with psoriatic arthritis (62 vs 21%, P c < 0.000001; OR = 6.1, AF = 0.83). In psoriatic patients a susceptibility region telomeric to HLA-C that includes C1―4―4 (56 vs 22%, P c < 0.0002; OR = 4.39, AF=0.77), OTF3 (85 vs 60%, P c < 0.0002; OR = 3.7, AF = 0.73) and HCR (63 vs 26%, P c < 0.00001; OR = 3.8, AF = 0.74) was observed. In psoriatic arthritis patients the susceptibility region was delimited by HLA-C and C1―4―4 (384 allele, 56 vs 22%, P c < 0.0002; OR = 4.37, AF = 0.77). Conclusions. Comparing the susceptibility regions associated with the two diseases, an overlapping interval of 100 kb between HLA-C and OTF3, which might contain the psoriasis gene, can be defined.

Our aim was to investigate whether different human leukocyte antigen (HLA) genes might be associated with hepatitis C virus (HCV) infection. DNA obtained from 141 Spanish patients with HCV infection (48 with alanine aminotransferase levels in the range considered to be normal, 47 with liver cirrhosis, and 46 with hepatocellular carcinomas [HCCs]) and from 116 control subjects were typed for HLA-B, HLA-DRB1, and HLA-DQB1 alleles, as well as for major histocompatibility complex class I chain-related gene A (MICA) transmembrane polymorphism. The frequency of HLA-DR11 was increased in HCV carriers, compared with patients with end-stage liver disease (ESLD) (corrected P value [P c ], .0002) and, especially, with patients who c had HCC (P c =.003). The frequency of the HLA-B18 allele was increased in patients with HCC, and the allele c was absent in HCV carriers (P c =.003). The MICA-A4 allele was overrepresented in patients with HCC, c compared with HCV carriers (P c =.0002). The DR3/MICA-A4/B18 haplotype was associated with HCC c (P c =.01). In conclusion, HLA-DR11 seems to be protective against the development of severe forms of c infection, and the DR3/MICA-A4/B18 haplotype may be an important factor in the progression to the most severe HCV-infection status.

To investigate the contribution of HLA class I alleles in the susceptibility to primary ankylosing spondylitis (AS) in West African patients living in Togo.A large epidemiologic analysis of 9,065 West African rheumatology patients living in Togo was performed in order to identify those who had AS. Eight Togolese patients with AS were identified. HLA was typed by polymerase chain reaction using sequence-specific oligonucleotide probes. DNA typing was also performed on a control population of 85 healthy subjects matched for ethnic background.A significant association between AS and B*14 was identified. This allele was found in 62.5% of the AS patients (odds ratio 69), but was carried by only 2% of the healthy controls. Analysis for B14 subtypes showed that B*1403 was the predominant allele in AS patients (odds ratio 171), and that this allele was absent in healthy controls. B27 was virtually absent, being observed in only 1 AS patient (B*2705).HLA-B*1403 shows the B27 "supertype" motif and may exert an effect on AS susceptibility according to the arthritogenic peptide model. The association of B*1403 with AS has not previously been reported in either population.

MICB is a member of the MIC (MHC class I chain-related gene) family. Sixteen MICB alleles have been described; however, the functional relevance and population distribution of MICB alleles or their potential association to disease has not yet been evaluated. In this study, we have developed a PCR system using sequence-specific primers (PCR-SSP) that allows unambiguous amplification of all MICB alleles. This approach has been applied to type 100 healthy unrelated individuals from the Spanish population. The extent of polymorphism in this population is lower than that initially expected, and only nine alleles were detected. The alleles MICB01021 (46%), MICB0103101 (13.5%), MICB0104 (13.5%) and MICB0106 (12.5%) were found to be the most frequent alleles. HLA-B and MICA transmembrane polymorphism typing were also performed in this population. Our data showed that MICB is in linkage disequilibrium with MICA and even with HLA-B. Thus, the linkage disequilibrium with MICA and HLA-B suggests that MICB is a potential candidate for those diseases classically associated with HLA class I alleles.

Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor-alpha (anti-TNF-alpha), has been effective in the treatment of patients with active Crohn's disease and with fistulas. We investigated the effect of infliximab on circulating cytokines and acute phase proteins in patients with fistulas to determine the clinical response to anti-TNF-alpha.A total of 36 patients with fistulizing Crohn's disease were selected for study. Serum from patients was drawn before the infusion on day 0 and at wk 2, 4, 6, 8, and 10 after completion of treatment. Circulating concentrations of TNF-alpha, interleukin-1beta (IL-1beta), and IL-6 were measured by ELISA. The functional activity of circulating TNF-alpha was assessed by the WEHI 164 TNF-alpha bioassay. Acute phase proteins were also determined.Elevated TNF-alpha, IL-1beta, IL-6, and acute phase proteins were observed in patients with Crohn's disease. Of the patients with fistulas, 22 (61.1%) responded to treatment. Before receiving infliximab, higher levels of serum TNF-alpha were found in patients who did not respond to infliximab compared with those who did (median interquartile range 26, 0-245 pg/ml; n = 14 vs 0, 0-22 pg/ml, n = 22). Patients showed no change in circulating levels of TNF-alpha during the course of the study.This treatment produces a clinical improvement in about two-thirds of CD patients with fistulas. The circulating levels of TNF-alpha are associated with the response to infliximab and could help to identify patients who would benefit from anti-TNF-alpha treatment.

The distribution of B27 alleles (B*2701-23) was characterized by PCR-SSP in ankylosing spondylitis and related spondyloarthropathies (SpA) in a sample of B27 positive patients from northern Spain. Six B27 alleles were identified: B*2705,02,03,07,08 and B*2713. B*2705 and 02 were the most common alleles in the SpA studied: ankylosing spondylitis (AS) (n = 89), reactive arthritis (ReA) (n = 11), psoriatic arthritis (PsA) (n = 29), and inflammatory bowel disease (IBD) (n = 21). B*2707 and B*2708 were found in PsA patients and B*2703 in one patient with IBD. B*2713 was identified in a healthy control family. B*2713 has not been reported to be represented in either ethnic group. Thus, this population shows higher levels of B27 diversity than other Caucasian groups.

To analyze the genetic contribution of HLA in development of psoriatic arthritis (PsA) and to study whether MICA is primarily associated with PsA or whether its association is secondary to linkage disequilibrium with centromeric genes, such as MICB, TNFA, or HLA-DRB1.DNA samples from 81 Spanish patients with PsA and 110 healthy controls were examined by polymerase chain reaction (PCR) sequence-specific primers to type HLA-Cw and HLA-DRB1, PCR sequence-specific oligonucleotides to determine HLA-B, and PCR restriction fragment length polymorphism for tumor necrosis factor-alpha promoter polymorphisms at positions -238 and -308. Analysis of microsatellite polymorphisms in the transmembrane region of MICA and in intron 1 of MICB was also carried out.HLA-Cw*0602 was significantly increased in PsA [60% vs 17%; p(c)0.00002, OR 7.33, etiological fraction (EF) 0.52]. MICA-A9 (60% vs 30%; p(c) = 0.0002, OR 3.57, EF 0.43) and the microsatellite MICB-CA-22 allele (23% vs 7%; p(c) = 0.028, OR 3.9, EF 0.17) were also significantly increased in PsA. MICA-A9 was in linkage disequilibrium with MICB-CA-22 (delta = 0.6). The association of MICA-A9 was independent of MICB-CA-22 and Cw*0602, since it was also associated in MICB-CA-22 negative (p(c) = 0.0015, OR 2.96, EF 0.34) and in Cw*0602 negative patients (p(c) = 0.034, OR 2.83, EF 0.34). TNFA and DRB I alleles were not significantly associated with PsA.Cw*0602 and MICA-A9 appear to be the strongest genetic susceptibility factors for PsA. However, MICA-A9 was associated independently of Cw6. HLA-B alleles and MICB-CA22 are associated secondarily to linkage with MICA. TNFA and HLA-DRB1 were not associated with PsA susceptibility, and our data suggest that their reported association may only reflect the linkage disequilibrium with MICA-A9 among the different populations studied.

The increased risk of developing hepatocellular carcinoma in hereditary hemochromatosis has been associated with cirrhosis and hepatic iron overload. The aim of this study was to investigate the association between HFE gene mutations (C282Y, H63D) and hepatocellular carcinoma in patients with alcoholic and virus-related cirrhosis.Serum markers of iron status and HFE mutations were determined in 179 patients with alcoholic cirrhosis and 98 patients with hepatitis B and/or hepatitis C virus-related cirrhosis. A total of 43 patients with alcoholic cirrhosis and 34 patients with virus-related cirrhosis had hepatocellular carcinoma. The control group consisted of 159 healthy bone marrow donors.No differences were found in the frequencies of mutations among patients with alcoholic cirrhosis, those with virus-related cirrhosis, and the control subjects. However, nine (20.9%) of the 43 patients with alcoholic cirrhosis and hepatocellular carcinoma were heterozygous for the C282Y mutation, compared with six (4.4%) of the 136 patients without tumor (p = 0.002). This difference was not found in patients with virus-related cirrhosis, with or without hepatocellular carcinoma, or the H63D mutation. The transferrin saturation was the only serum iron marker the value of which was significantly higher among C282Y heterozygotes with alcoholic cirrhosis compared to those without mutation.The high frequency of heterozygosity for the C282Y mutation in patients with alcoholic cirrhosis plus hepatocellular carcinoma suggests that the presence of this mutation could be associated with an increased risk of developing hepatocellular carcinoma in these patients.

A polymerase chain reaction-sequence-specific primer (PCR-SSP) method which distinguishes all B27 alleles described at present (B*2701–23) has been developed. The distribution of B27 alleles was characterised in six different Asian populations. HLA-B*2705, 02, 04, 07, 22 (formerly B*2706) subtypes found in Asian populations differ in their ethnic distribution, which may be the result of different genetic and geographic origins. Furthermore, two novel B27 alleles were found in this study. B*2714 was identified in two Siberians, one of whom was a patient with ankylosing spondylitis. B*2715 was found in two patients with ankylosing spondylitis in Thais. These associations have not previously been reported in either ethnic group.