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1. Introduction
Immune cells get educated in the thymus during development to recognize self antigens so that there are no immune responses against self antigens. However, whenever they encounter non-self antigens like bacteria or viruses, they are recognized as non-self and immune response takes place against them to save us from infections. While the basic purpose of the immune response is to save us from infections, something goes awry in some cases such that the self antigens are recognized as foreign by one’s own immune cells which attack the cells /organs containing those antigens presuming them to be foreign. This results in auto-immune disorders like Type 1 diabetes, vitiligo or hypoparathyroidism, the focus for the present chapter. All these disorders are complex, multi-factorial, organ specific disorders where auto-immune responses have been implicated due to presence of auto-antibodies and auto-antigen specific T cells in the peripheral circulation of the patients. Although what triggers the autoimmune responses in these disorders is not clearly understood, association with certain major histocompatibility complex (MHC) alleles has been considered a hallmark of autoimmune disorders [1] since they have a role in antigen presentation that orchestrates the antigen specific adaptive immune responses.
Major Histocompatibility Complex (MHC) is a set of glycoprotein molecules present on the cell surface of nucleated cells encoded by several polymorphic genes localized on chromosome 6 of man. In human, MHC is known as Human leukocyte Antigens (HLA). MHC region is spread over 3.84 megabases of chromosome 6p21.3 and is the most gene dense region of the human genome with 224 genes. 128 of these 224 genes are known to be expressed. And 40 % of these genes have immune related functions [2]. HLA constitutes a small part of the MHC region. Major function of HLA molecules is to present antigenic peptides to T cells. HLA can be broadly classified into two major classes: class-I and class-II. HLA class-I genes are HLA-A, -B and –C. These are classical class-I genes which are very polymorphic with 2365, 3005 and 1848 alleles respectively.
The MHC class-I molecules are present on the surface of all nucleated cells and present antigenic peptides to the CD8+ cytotoxic T cells. MHC class-I molecule is a hetero-dimer of a heavy and a light chain. The molecular weight of the heavy alpha chain is about 40-45 KDa and that of the light chain, beta 2 microglobulin (β2m) is 12 KDa [3]. The genes for the alpha chains are encoded on chromosome 6. However, the gene for β2m is encoded on human chromosome 15. The heavy chain of the MHC class-I molecule has three domains alpha 1 (α1), alpha 2 (α2) and alpha 3 (α3). Alpha 1 (α1) and alpha 2 (α2) domains are the most polymorphic domains since they constitute the peptide binding groove of the MHC molecule. These polymorphic domains are encoded by exons 2 and 3 of the genes encoding MHC class-I alpha chain which has in total 8 exons. The peptides that are presented by the MHC molecules have allele specific motifs i.e., certain peptides can be presented by certain MHC molecules. The affinity of the peptide to bind to the peptide binding groove is determined by the anchors present on the peptide binding groove where the peptides go and bind through hydrogen bonds. Specific motifs or the amino acid residues present in the pockets of the peptide binding grove which are involved in binding the side chains of complimentary residues of the peptide determine which peptides would bind to which MHC molecule [4, 5]. Pockets B (key residues at positions 9, 45, 63, 67, 70 and 99) and F (key residues at positions 77, 80, 81 and 116) of alpha chain are the main anchors which engage the peptides at their amino acid positions 2 and the C-terminus [6]. However, several alleles of the MHC share peptide binding specificities i.e. similar peptides may be presented by different MHC molecules. These alleles are clustered in supertypes [6].
HLA class-II molecules are expressed on antigen presenting cells like macrophages, dendritic cells, B cells, thymic epithelium and activated T cells [7]. MHC class-II molecules present antigenic peptides to the CD4+ T helper cells (Th cells) which in turn initiate a cascade of immunological events that result in activation of CD8+ cytotoxic T cells and B lymphocytes [2]. CD4+ T helper cells get activated when a non-self antigen is presented to them. T helper cells are of two types T helper 1 (Th1) and Th2. Th1 cells secrete cytokines like Interferon gamma and TNF-alpha which are involved in cell-mediated immune responses as they activate the cytotoxic T cells which have already seen the antigen in the context of MHC class-I. Th2 cells, on the other hand, secrete IL-4, IL-5 and/or IL-6 which are involved in humoral immunity as they activate the B cells to become plasma cells which make the antibodies against antigen they have seen. Thus an immune response takes place which varies in strength depending on the host factors and the peptides being presented.
The classical MHC class-II glycoproteins in humans are HLA-DR, -DP and –DQ. The MHC class-II molecule is a heterodimer of two polypeptide chains: an alpha (25-33 KDa) and a beta chain (24-29KDa) [8, 9]. Unlike MHC class-I, both alpha and beta chains of the class-II molecule are encoded on chromosome 6. DRB1 gene encodes DR beta chain while DRA1 encodes DR alpha chain with 1355 DRB1 alleles and 7 DRA1 alleles. Similarly DQB1 and DPB1 encode beta chains of DQ and DP molecules with 416 and 190 alleles respectively and DQA1 and DPA1 encode the alpha chains of DQ and DP molecules with 51 and 37 alleles respectively [10, 11].
Besides the classical class-I and class-II genes there are several non-classical HLA genes with specialized functions and also pseudo HLA genes present in the MHC region. However, they will not be discussed here since their roles are not very clearly understood in autoimmunity.
A recurring theme of several autoimmune disorders is the aberrant presentation of self antigens to the immune system that triggers downstream perturbations. Under normal circumstances most of the MHC molecules are occupied by self peptides and the T cells are tolerized against them during thymic education so that auto-immune responses do not take place, however, sometimes there is a break in the tolerance resulting in recognition of self as non-self by the immune system which results in an auto-immune response. This break in tolerance could be due to low expression of some antigens in the thymus which may result in self-reactive T cells to reach the peripheral circulation. Or it could be due to escape of self-reactive T cells from clonal deletion during T cell development. Since associations with MHC alleles have been considered a hallmark of autoimmune disorders due to their role in antigen presentation, we have studied HLA alleles in two common and one rare autoimmune disorders: Type1 diabetes, vitiligo and hypoparathyroidism.
2. Patients and controls
DNAs were extracted using standard protocol from 10 ml of blood from type 1 diabetes (N=211), vitiligo (N=1404), hypoparathyroidism patients (N=134) and 902 normal healthy controls from the same ethnic background after obtaining informed consent. All the patients attending diabetes of young clinic were carefully assessed and categorized as type 1, type 2 and fibrocalculous pancreatopathy as per the recent classification by American Diabetes Association expert committee [12, 13]. All of the T1D subjects included in the study required insulin for glycemic control and 51 of them had history of ketosis at presentation. Insulin requiring patients with fibrocalculous pancreatopathy and subjects with diabetes in whom glycemic control was achieved with diet and oral hypoglycemic agent were excluded from the study [12, 14].
Vitiligo group consisted of 1404 North Indian patients enrolled at Dr. Ram Manohar Lohia Hospital (RMLH), and All India Institute of Medical Sciences (AIIMS), New Delhi Diagnosis of vitiligo was based on clinical examination done by dermatologists. Clinically, the cases were classified as having Generalized (Vulgaris, Acrofacial, Universalis) or Localized (Focal, Acral, mucosal and segmental) forms of vitiligo. The replication study was done on 355 vitiligo cases from Gujarat, a state in west of India [15].
Idiopathic hypoparathyroidism group consisted of 134 unrelated patients who attended the endocrine clinics of All India Institute of Medical Sciences during 1998-2011. The diagnosis of IH was based on presence of hypocalcemia, hyperphosphatemia, low serum intact PTH, normal renal function and serum magnesium levels. Patients with post surgical hypoparathyroidism were not included. Patients with clinical features of APECED syndrome indicated by mucocutaneous candidiasis or presence of adrenocortical autoantibody were excluded from the study[16].
Nine hundred and two ethnically matched unaffected controls from North India were used for all three studies and 441 ethnically matched unaffected controls from Gujarat were studied in the replication study for vitiligo only. None of the unaffected controls had personal or family history of T1D, vitiligo, hypoparathyroidism or any other autoimmune or infectious disease.
All Cases and control samples were collected after obtaining informed consent and Institutional Human Ethics Committee’s clearance from all the institutes/Hospitals involved, following declaration of Helsinki protocols.
3. Study of HLA -A, HLA-B and HLA–DRB1 alleles
DNA extraction was carried out by standard procedures from fresh whole blood samples collected in anticoagulant EDTA. Alleles of
4. Statistical analysis
Frequencies of alleles in the patient samples were compared with their respective unaffected controls using Chi-square analysis and the strength of associations was estimated by odds ratio (OR) and 95% confidence interval using Stata 9.2 statistical program. Fisher’s exact test was used when the numbers were five or less in any group i.e. in cases or controls for any allele. In such cases, Odds ratios were calculated using Woolf’s method [19] with Haldane’s [20] modification as described earlier [21].
5. Type 1 diabetes
Type 1 diabetes (T1D) is an incurable, multi-factorial and complex autoimmune disorder characterized by the loss of insulin producing beta cells of the pancreas. This results in abnormal metabolism of glucose that may be detrimental for several other complications like ketoacidosis, retinopathy, nephropathy and even cardio-vascular diseases and pre-mature deaths [22]. World-wide disease affects 1 in 300-400 children [23]. The incidence in South India has been reported to be 10.5/100,000/year [24]. In North India, a higher prevalence in urban (26.6/100,000) as compared to rural areas (4.27/100,000) has been reported with a total prevalence of 10.20/100,000. T1D develops as a result of complex interaction of many genetic and environmental factors leading to autoimmune destruction of the insulin producing Pancreatic Beta cells. While 20 genomic intervals have been implicated for the manifestation of the disease [22], role of an intricate network of the products of these genes cannot be ruled out. However, unraveling different factors involved and how they interact in integrated networks is like solving a zig-saw puzzle which is the aim of our studies [12, 14, 17]. However, in this chapter we will be concentrating on MHC associations and their implications only.
When the patients report to the clinician, he is left with no option but to give daily insulin injections since most of their pancreatic beta cells are already destroyed. So, if we want to stop autoimmune responses in the people who are predisposed to get T1D, we need to identify the prediabetics before the onset of the disease and device ways to inhibit autoimmunity in them. This is possible by using genetic predisposition criteria to get the disease.
We have studied the frequencies of MHC class-I alleles for HLA-B locus and MHC class-II alleles for HLA-DRB1 and DQB1 loci in patients with Type 1 diabetes and normal healthy controls using polymerase chain reaction followed by hybridization with sequence specific oligonucleotide probes (PCR-SSOP). DNAs were isolated from peripheral blood mononuclear cells (PBMCs) from patients and healthy controls using standard protocol. The second and third exons of the HLA-B gene and second exons of HLA-DRB1 and DQB1 genes were amplified using PCR and hybridized with oligonucleotide probes and the hybridization pattern with different probes was used to identify the alleles present in a sample. The results showed that
Figure 1.
Distribution of
HLA-DRB1 and DQB1 are in strong linkage disequilibrium. We also studied the alleles of
Figure 1d shows the homozygosity and heterozygosity of
Figure 1 e shows the
Thus our studies show a significant increase of HLA class-I and II alleles which may have a role in auto-antigen presentation to CD8+ and CD4+ T cells respectively.
6. Vitiligo
Vitiligo is a depigmenting disorder of the skin caused by autoimmune destruction of pigment producing cells called melanocytes. It effects 0.5-1 % of the world population [42], while in India the incidence varies from 0.25 to 2.5% [43, 44] in most ethnic groups, however, it has been reported to be 8.8% in populations from western states of Gujarat and Rajasthan [45]. Vitiligo manifests in several forms which can be broadly classified in two clinical subtypes: generalized and localized [42]. While precise etiology of vitiligo is not very well understood, several hypotheses have been proposed which include autoimmune [46], neural [47], auto-cytotoxic [48] and genetic hypotheses [49]. However, autoimmune hypothesis gets credence due to co-occurrence of other autoimmune diseases in vitiligo patients in some cases, presence of auto reactive T cells and circulating auto-antibodies in the patients [46, 50-55]. The role of genetic factors has been suggested due to the fact that 7% of first-degree relatives of vitiligo develop the disease. [56, 57].
Recent genome wide studies [58, 59] have shown that several
Our study showed a lot of diversity in number and frequencies of HLA alleles in patients and controls, with 78, 160 and 106 alleles in cases and 68, 111 and 94 alleles in controls for
Figure 2.
HLA-A, B and DRB1 loci alleles significantly increased in all vitiligo, generalized vitiligo and localized vitiligo patients when compared with healthy controls in North Indian and Gujarat patients. * denotes alleles that show statistically significant increase or decrease in the frequencies of the depicted alleles.
Removal of
Figure 3.
Amino acid signatures for the peptide binding pockets of HLA molecules for DR beta1 chain in all vitiligo, generalized vitiligo and localized vitiligo patients from North India and Gujarat. Amino acids shown in red are significantly increased in vitiligo patients while amino acids shown in green are significantly reduced in vitiligo patients as compared to controls and those in black are not significantly different from controls (Singh et al., JID, 2012).
We further studied the amino acid signatures of the peptide binding pockets of DRB1 in vitiligo cases and unaffected controls Eleven residues representing integral parts of peptide binding pockets of DR beta chain were analysed at positions 26, 28, 30, 37, 47, 67, 70, 71, 74, 77 and 86 [62]. The protein sequences were downloaded for all the alleles observed from the HLA database (http://www.ebi.ac.uk/cgi-bin/imgt/HLA/align.cgi) and the amino acids present at the aforesaid positions were compared in patients with controls. Figure 3 shows the amino acid residues at the aforesaid positions that were either significantly increased or decreased in all vitiligo patients, generalized and localzed vitiligo patients when compared with controls. The results show that Glu28β, Leu30β/Arg30β Phe37β, Tyr47β, Ile67β, Asp70β, Arg71β, Gln74β, Thr77β and Gly86β make the molecular signature of the peptide binding pockets of DRB1 for predisposition to develop vitiligo in both the initial as well as in the replication study (Figure 3). Asp28β, Tyr30β/Cys30β, Ser37β, Phe47β, Leu67β, Gln70β, Lys71β, Ala/Arg74β, Asn77β and Val86β make the molecular signature for the protection from Vitiligo in both North India and Gujarat. [15].
We observed subtle differences in the molecular signatures of the peptide binding pockets of DR beta chain in localized and generalized vitiligo. Localized vitiligo patients show similarities in the amino acid signatures with not only generalized vitiligo but also with healthy controls probably responsible for localized distribution of the lesions in them. Amino acid signature at positions Glu28β, Leu30β, Phe37β, Tyr47β and Gln74β in the localized vitiligo patients is similar to generalized vitiligo in both the initial and replication study. However, the amino acid signature similar to healthy controls were observed at positions Arg30β/Cys30β, Ser37β, Ile67β/Leu67β Asp70β, Ala74β in North Indians and Cys30β, Ser37β, Asp70β, Arg71β/Lys Ser71β, Ala74β/ Arg74β and Thr77β /Asn77β in Gujaratis [15].
Most of the studies previously have been done on Generalized vitiligo which has been considered to be an autoimmune disease. We showed for the first time that both generalized and localized vitiligo have the same predisposing MHC alleles i.e.,
7. Idiopathic hypoparathyroidism
Idiopathic hypoparathyroidism (IH) is a rare endocrine disease where parathyroid gland is functionally impaired resulting in subnormal PTH secretion, hypocalcemia, hyperphosphatemia and associated complications [63]. While it may be an autoimmune disorder [63], there is hardly any evidence to confirm the autoimmune etiology of the disease. Since there was no comprehensive study on the immunogenetic basis of IH, we studied the association of
Just like vitiligo, we observed diversity in number and frequencies of HLA alleles with 23, 40 and 44 alleles in patients for
Associations of
Figure 4.
We constructed HLA haplotypes for HLA-A-B-DRB1 and HLA-A-B and HLA-A-DRB1 for 133 cases and 902 controls using Arlequin 3.5 program (http://cmpg.unibe.ch/software/arlequin35/). Haplotype
MHC molecules are extremely polymorphic, however, alleles with similar peptide binding pockets may be clustered in one group [6], called supertypes, such that HLA molecules in one supertype may present similar peptides[16]. Assignment of alleles in the supertypes have been done based on published motifs, binding data, shared repertoires of binding peptides and the amino acid sequences of different alleles at the peptide binding pockets [6]. Supertype A01 (which includes
Figure 5.
Amino acid signatures (single letter codes) of the peptide binding pockets and HLA supertypes of 23 HLA-A locus alleles observed in IH cases showing significant increase or decrease in the number of amino acids. N=259 indicates 259 alleles were observed in 134 patients which were compared with amino acid signatures of 1698 alleles from 902 controls.
While the amino acid residue at a particular position in different alleles in a supertype may not be the same, they would be similar in nature such that they would bind similar peptides. For instance, all the alleles falling in supertype A01 will bind small and aliphatic residues in the B pocket and aromatic and large hydrophobic residues in F pocket [6]. Thus, the nature of the shared amino acids and not amino acid per se constitutes the molecular signatures of the peptide binding groove of different alleles in a supertype.
The peptide binding groove of the MHC class-I molecules contain small pockets where the side chains of complimentary residues of the peptide bind [4]. Pockets B (key residues at positions 9, 45, 63, 67, 70 and 99) and F (key residues at positions 77, 80, 81 and 116) of alpha chain are the main anchors which engage the peptides at its amino acid position 2 and the C-terminus [6]. Since we observed a significant increase in an HLA-A locus allele (
MHC is the most polymorphic system of the man with more than 6000 alleles for different loci. With such a great diversity, association of particular
Our results suggest affinity of auto-antigenic peptides for predisposing MHC class-II and class-I molecules which may be involved in orchestrating (through CD4+ T cells) and implementing the autoimmune responses (through CD8+ T cells) in Type 1 diabetes, vitiligo and hypoparathyroidism.
Acknowledgments
We are thankful to the study participants: cases and the controls that provided blood samples for the study. Authors are thankful to Dr. Mitali Mukerji, IGIB, Delhi, for providing access to the Indian Genome Variation Consortium samples that have been used as unaffected controls in these studies. The projects were funded in part by grants from Department of Science and Technology (DST), Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India and partly by Core funds of National Institute of Immunology, New Delhi, India. Diabetes work was supported by Department of Science & Technology, New Delhi, India, grant No. SP/SO/B54/98. Vitiligo work was supported by grants for ‘Genetic and autoimmune factors associated with vitiligo’ (Grant number BT/PR6653/Med/12/258/2005) and the ‘Program support for Skin pigmentation and melanocyte-keratinocyte biology’ (grant number BT/01/COE/07/07) from the Department of Biotechnology, India. The hypoparathyroidism work was sponsored by Department of Biotechnology, grant number BT/PR15022/Med/30/589/2010. The patient sample for this work came from All India Institute of Medical Sciences (AIIMS), New Delhi and Dr. Ram Manohar Lohia Hospital (RMLH), New Delhi, India. We would like to thank Dr. R. Goswami, Department of Endocrinology and Metabolism, (AIIMS) for T1D and hypoparathyroidism samples. We would like to acknowledge Dr. H. Kar (RMLH), Dr. V. K. Sharma (AIIMS) and Dr. Somesh Gupta (AIIMS), the dermatologists for providing the vitiligo samples. We thankfully acknowledge Dr. Rasheedunnisa Begum and her team for providing vitiligo samples for the replication study from Gujarat. We would like to acknowledge the students and project fellows who have been involved in doing this work. Mr. Kapoor Chand’s technical support is acknowledged.
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