Immunogenetics: A Molecular and Clinical Overview: Clinical Applications of Immunogenetics

Clinical Applications of Immunogenetics: Immunogenetics: A Molecular and Clinical Overview, Volume II provides readers with an exclusive, updated overview of scientific knowledge, achievements and findings in the field of immunogenetics. In thirteen chapters, the book gives insights in new advancements and approaches in viral and autoimmune diseases. Specific chapters are dedicated to immunogenetic mechanisms in the treatment of immune disorders, cancer, neurological and neurodegenerative disorders. In addition, other chapters cover immunogenomics in precision medicine, clinical medicine and transplantation. Finally, a special chapter, COVID-19: A novel challenge to human immune-genetic machinery, updates on thoughts surrounding the pandemic.

• Contains exclusive information about global research on immunogenetics
• Provides a solid foundation to researchers wanting to work on immunogenetics and their application in different autoimmune, viral and infectious diseases
• Delivers information in a meticulous, attractive manner using pictures, illustrations and tables
• Gives insights into immunogenetics and its utility in therapeutics

• Language: English
• Publisher: Academic Press
• Release date: Mar 24, 2022
• ISBN: 9780323902519

Book preview

Preface

It is indeed a great pleasure to edit this book "Immunogenetics: A Molecular and Clinical Overview (Volume II): Clinical Applications of Immunogenetics. Immunogenetics is a rapidly increasing area of research that combines the two basic branches—genetics and immunology—and depicts the relationship between these. Understanding immunogenetic mechanisms is central to the perception of immunogenetic disorders and development of convenient novel therapies thereof as it finds genetic variations that disrupt normal immune pathways. This book has appealing features for a wider range of audience in the fields of immunology, genetics, immunogenetics, immunogenomics, and immunotherapeutics. Academicians, researchers, scientists, lecturers, physicians, instructors, and students may find the book useful as a guiding light and a single up-to-date source of knowledge. The book is divided into 16 chapters, which are embellished with graphics and tabulations to pique the reader’s attention. This book includes chapters based on the prognostic, diagnostic, and therapeutic utility of immunogenetics, phytoremedy of immunogenetic disorders, immunogenetics of human viral diseases, the potential of micro-RNAs as cancer immunotherapeutic modulators, immunogenetic perspective of inflammatory disorders, immunogenetic mechanism driving neurological and neurodegenerative disorders, immunogenetic application of human leukocyte antigens typing in clinical medicine, immunogenomics as a potential approach for precision medicine, immunogenetic factors involved in rheumatoid arthritis and immune therapies, and immunogenetic mechanisms in the treatment of cancer. The other interesting topics discussed in the book include transplantation immunogenetics, immunogenetics as a tool for the identification of novel therapeutic targets in immune disorders, and therapeutic approaches of immunogenetic molecules in inflammatory bowel disease management. However, one of the excellent attributes of the book is the inclusion of a chapter on Covid-19 pandemic entitled Covid-19: a novel challenge to human immune genetic machinery." Furthermore, this book offers special information regarding worldwide immunogenetics research and presents it in a comprehensive manner.

Chapter 1

Immunogenetics and its utility in therapeutics

Sofi Imtiyaz Ali¹, Alveena Ganai², Muzafar Ahmad Rather¹, Wajid Mohammad Sheikh¹, Showkat Ul Nabi³, Peerzada Tajamul Mumtaz¹, Sanju Mandal⁴, Qudratullah Kalwar⁵, Mehvish Altaf⁶, Tajali Sahar⁷ and Showkeen Muzamil Bashir¹*,    ¹Biochemistry and Molecular Biology Lab., Division of Veterinary Biochemistry, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, India,    ²Division of Veterinary Parasitology, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Jammu, Jammu, India,    ³Large Animal Diagnostic Laboratory, Department of Clinical Veterinary Medicine, Ethics & Jurisprudence, Faculty of Veterinary Sciences & Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Srinagar, India,    ⁴Department of Veterinary Biochemistry, College of Veterinary Science and Animal Husbandry, Jabalpur, India,    ⁵Department of Animal Reproduction Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Sakrand, Pakistan,    ⁶Department of Food Technology, IUST Awantipora, Pulwama, India,    ⁷Clinical Research Laboratory, Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India*, Corresponding author.

Abstract

Immunogenetics is the study of the interaction between genetics, the immune system, hereditary immune response regulation, vulnerability to disease, immune system bioinformatics, arrangement of immunologically significant molecules, reproductive biology immunogenetics, separation of tissues, and development. Immunogenetics is composed under one framework, including sequences, nucleotides, genes, proteins, immunoglobins, or antibodies like T-cell receptor, major histocompatibility complex (MHC)/human leukocyte antigen (HLA). Immunogenetics is useful for diagnosis, therapeutics, and engineering autoimmune disease acquired immunodeficiency diseases (like AIDS, etc.), and various other infectious diseases. This chapter MHC and HLA immunogenetics and determine its therapeutic capability with combined efforts to diagnose, prevent, and treat various infectious diseases.

Keywords

Immunogenetics; major histocompatibility complex; human leukocyte antigen; T-cell receptor; acquired immunodeficiency diseases

Introduction

The term immunogenetics includes all organism processes that are regulated and influenced by genes that are also crucial in the organism’s immunological protection reactions. The co-evolution between humans and pathogens has produced severe assortment in some genes, particularly the human leukocyte antigens (HLAs) (Hedrick, 2002; Jeffery & Bangham, 2000; Pierini & Lenz, 2018; Spurgin & Richardson, 2010), producing the utmost polymorphic HLA loci in the human genome. The word immunogenetics is focused on both immunology and genetics and is described as a genetic sub-discipline, which interacts with the genetic basis of the immune response (immunity). In 1980, Baruj Benacerraf, Jean Dausset, and George Davis Snell won the first Nobel Prize in the field of immunogenetics for the discovery of genetically defined cell surface structures that regulate immunological reactions (Gonzalez-Galarza, Christmas, Middleton, & Jones, 2010).

The major objective of immunogenetics is to preclude and treat autoimmune diseases, scan and map the human genome, and compare genes due to the loci’s allelic diversity. Thus, the genetic intricacy of various conditions showed by modern molecular methods emphasized that genetic markers further require a fuller understanding of polygenic or widespread multifactorial diseases (Risch & Merikangas, 1996). Few investigators also calculated the genetic aspect of differential immune responses and evaluated the actual assessment of the main histocompatibility complex (MHC) and non-MHC genes (Jepson, Banya, Sisay-Joo, Hassan-King, & Nunes, 1997) on several vertebrates. HLA is used interchangeably with MHC in humans.

Immunogenetics

Both antigens (HLA and MHC) are responsible for preventing inbreeding or genetic material disorder that is remarkably similar in an organism. In genetic makeup, they favor diversity and are accountable for collaboration in kin identification, dual recognition, and matching of transplants. Only the first and second groups of antigens are responsible for identifying and responding to any cell, local or foreign. Class I antigens struggle with killing local cells that are alien or infected, except red blood cells. Type II antigen mediates unique vaccination of B cells, macrophages and antigen-presenting cells (APCs). Therefore, MHC and HLA serve as safety defenses for the body of an individual (Stamatelos & Anagnostouli, 2017).

Classification of major histocompatibility complex

The MHC located in the short arm of chromosome 6(6p21.3) represents the most versatile gene cluster in the completely human genome. HLA based on the structure and role of gene products consists of Class I, Class II, and Class III. HLA-Class I gene products (HLA-A, -B, and -C) play a key role in presenting endogenous peptides to CD8+T cells, whereas HLA-Dr, -DP, and-DQ class II molecules have limited expressions and are responsible for processing exogenous peptide to CD4+T cells for presentation. In contrast, the Class III region includes genes encoding immune regulatory molecules, for example, tumor necrosis factor (TNF), complementary C3, C4, C5 factors, and heat shock proteins. (Cruz-Tapias, Castiblanco, & Anaya, 2013) (Fig. 1.1).

1. Class I MHC GENE: It consists of a 44 kDa non-covalently connected heavy polypeptide chain with a smaller 12 kDa peptide called β2-microglobulin. The large portion of the heavy chain is structured into three global domains (alpha1, alpha2, and alpha3) protruding from the surface of the cell; a hydrophobic segment anchors the membrane molecule, and the C-terminus is brought into the cytoplasm by a short hydrophilic sequence (Albring, Koopmann, Hämmerling, & Momburg, 2004). A varying and constant region is present in the heavy chain. The portion of the variable is quite pleomorphic and polymorphism of such molecules is essential in the identity of self and non-self. This gene encodes almost all nucleated cells on the surface of the glycoprotein. The appearance of endogenous peptide antigens to CD8 + T cells is the main feature of the class I gene products. On cytotoxic T lymphocytes (CTLs) surface, T-cell receptors (TCRs) interact with MHC class I peptides where CTLs are activated, inducing target cell lysis and T-cell proliferation. This complex also interacts with natural killer (NK) receptors, such as killer immunoglobins such as receptors (KIRs), which can damage the components of the self and control NK cell effector functions (Kim, 2003).

2. Class II MHC GENE: Transmembrane glycoproteins consists of molecular weight chains of 33-kDa alpha and β polypeptides and a chain of 28-kDa β connected to non-covalent interactions. Two external domains found in the Class II molecule are α1 and α2 domains in one chain and β1 and β2 domains in the other have substantial sequence homology with class I parts (Babbitt, Allen, Matsueda, Haber, & Unanue, 1985). Structural experiments have shown that the β2 and β2 domains adjacent to the cell membrane assume the characteristic Ig fold, while the β1 and β1 domains mold the peptide-binding groove for the processed antigen. It also encodes glycoproteins primarily expressed in APCs (macrophages, dendritic cells, and B cells), where exogenous antigenic peptides are mostly present in CD4 + T cells (Castellino, Zhong, & Germain, 1997).

a. Macrophages: Extracellular peptides or pathogens form a vesicle called phagosome, which combines digestive substances with lysosomes to obtain their antigens. MHC class II molecules guide them to the external surface of the cell, where T-helper (Th) cells identify these antigens and after recognition will drive further macrophages into phagocytic pathogens (Savina & Amigorena, 2007).

b. B lymphocytes: The foreign antigen binds the immunoglobins to B cell surface to brace the absorbed antigen for MHC class II presentation. Complex Peptide-MHC II has Th cells, which encourage plasma antibody-producing cell proliferation. Antibodies formed by cells join the bloodstream and form complexes with corresponding antigens, resulting in complexes of antigen-antibodies. Thus, MHC II class molecules and I helps in activating cell-mediated and antibody-mediated immune responses. (Iwasaki & Pillai, 2014).

3. Class III MHC: These genes are encoded with many distinct proteins, including those with immune functions, components of the complementary mechanism, and inflammatory molecules. Complementary components C2 and C4 and factor B (B) are encoded by genes in the MHC. These proteins are produced in the liver and extrahepatic mononuclear phagocytes (Gruen & Weissman, 1997).

Figure 1.1 Structural difference of cytotoxic T cell and helper T cells associated with MHCI and MHC-II.

Distribution of major histocompatibility complex

Both nucleated cells express class I molecules on lymphoid cell and less on hepatic, liver, kidney, and marginally on the brain and muscle cells. HLA-A and B are no longer present in humans and hold HLA G that may not appear with other body cells on the surface of the villous trophoblast. Class II molecules are often limited in their presentation, were active only on APCs such as B-cells, dendritic cells, macrophages, and thymic epithelium (Kambayashi & Laufer, 2014). They produces class II and increased class I expression when stimulated by interferon- γ, capillary endothelia, and several epithelial cells in tissues other than the thymus. They act as cell surface markers that cause cytotoxic and helper T-cells to be signaled by infected cells.

Importance of major histocompatibility complex

1. Antibody molecules immediately interact with the antigen, but the TCR, which is unique to the antigen, recognizes the only antigen presented by MHC molecules on APC but the antigen must be presented (Janeway, Travers, Walport, & Shlomchik, 2001).

2. The TCR for the MHC molecule is also specific. If the antigen is treated in vitro (usually in an experimental situation) with another allelic version of the MHC molecule, there is no TCR recognition. This phenomenon is known as MHC restriction. CD8+ CTLs recognize class I MHC molecules associated peptide antigens, while CD4+ helper T cells recognize class II-associated peptide antigens (Koopmann et al., 2000).

Classification of human leukocyte antigen complex

The key function of HLAs is to supply the immune system with peptides and to organize cellular and humoral immunity. In transplants, both hematopoietic stem cells and solid organ transplants, like renal transplants, the HLA system plays a significant role. It is also essential for transfusion-related complications such as platelet refractoriness, febrile non-hemolytic transfusion reactions, acute lung damage associated with transplants and transfusions, and graft versus host disease (GvHD) (Deshpande, 2017). The HLA gene complex found on the short arm of chromosome 6 includes many genes important for immune function (Fig. 1.2). HLA typing is also known as Tissue typing as HLA antigens are present on maximum body tissues. Histocompatibility is not the only feature of HLA antigens, as stated by Erik Thorsby. This complex may better be called a significant immune response complex (Thorsby, 2009).

Figure 1.2 Map of the HLA gene complex found on the short arm of chromosome number 6 in humans.

The HLA complex of genes is classified into three classes as follows:

1. Class I (HLA-A, HLA-B, and HLA-C): They are represented on the surface of most nucleated body cells, present in plasma in a soluble state and are adsorbed on the platelet surface. In mature red cells, designated as Bennett-Good speed (Bg) antigens, only vestigial quantities exist (Mark, 2005). Only vestigial portions exist in mature red cells, designated as Bg antigens. Class I antigens have a molecular weight of 57,000 daltons and consist of two chains, a short arm of chromosome 6 encoded heavy glycoprotein chain (45,000 daltons) and a medium-chain and β2-microglobulin molecule (12,000 daltons) encoded on chromosome 15 by a mutation. There is no binding of β2-microglobulin to the cell membrane (Klein & Nikolas, 2007).

2. Class II (HLA-Dr, HLA-DQ, and HLA-DP): They form part of the HLA complex in the HLA-D region. There are two amino acid domains in each chain, of which the outermost domain comprises the vector area of Class II alleles (Blum, Wearsch, & Cresswell, 2013). Class II antigen tissue distribution is limited to immunocompetent cells such as B-lymphocytes, macrophages, endothelial cells, and activated T-lymphocytes. Although Class II antigens trigger the general immune response, they are found in immunologically active cells and not in all tissues. In class I and class II molecules, the peptide-binding groove is essential for HLA molecules’ functional features (Kaufman, 2018).

3. Class III: Complement loci that encode the complement mechanism and TNFs alpha and beta for C2, C4, and factor B.

Importance of human leukocyte antigen allele system

In organ and hematopoietic stem cell transplantation, the HLA system is used to develop vaccines, particularly cancer vaccines. The necessity for global cooperation was documented early due to the unusual genetic variation and heterogeneity of HLA across various world communities. The International Histocompatibility Workshops (Charron, 1997) introduced a new model for coordinating and translating contemporary biomedical research over 40 years ago. These combined approaches made it possible to exchange data together, exposing the degree of HLA diversity, demonstrated by the HLA nomenclature containing over 4,000 alleles.

Methods for detecting antigens and alleles

Molecular sequence-specific primers (SSP) and sequence-specific oligonucleotide probes (SSOP) and cellular biology (micro lymphocytotoxicity and mixed lymphocyte culture) are considered for the identification of HLA antigens and alleles (Donadi, 2000). The HLA specificities in the diverse lymphocyte culture are characterized by cells having established phenotype and T lymphocytes for HLA-A, B and C and B-lymphocytes for HLA-Dr and -DQ antigens are used. HLA-DP antigens are not typified by any particular antiserum (Fernandes, Maciel, Foss, & Donadi, 2003) and molecular techniques never type the HLA antigens presented on the cell surfaces. After DNA extraction from the cells, it is amplified by the polymerase chain reaction (Fernandes et al., 2003). The HLA antigen distributed on cell surfaces never typed through molecular biology techniques. Therefore, by the SSP or the SSOP approaches, the HLA alleles’ typification may be achieved. Although oligonucleotide primers have unique sequences to identify a single allele or a group of alleles, the former has a special sequence of oligonucleotide probes intended to identify one or all the alleles in a group (Terasaki, 1969).

Human leukocyte antigen system nomenclature

The International Committee encourages annual conference to assign new identities to newly discovered genes or change the standard terminology of the HLA system (Donadi, 2000). The HLA prefix designates the HLA antigen, shadowed by the gene locus (e.g., HLA-A, HLA-Dr) and the antigen’s numerical designation (e.g., HLA-A1, HLA-A2). The nomenclature of the C locus includes the letter ‘w’ (e.g., HLA-Cw1, -Cw2) for distinguishing from the complement scheme (e.g., C1, C2) (Klein & Nikolas, 2007). The molecular biology methods are used to identify the alleles. The HLA prefix designates the HLA class II alleles and its gene locus (e.g., HLA-DQ, HLA-Dr, HLA-DP), and letters ‘A’ or ‘B’ denotes the HLA-DP and HLA-DQ (e.g., HLA-DQA, HLA-DQB) polymorphic α and β chains, while letter ‘B’ only designates the HLA-Dr as it is the only polymorphic chain (e.g., HLA-DRB). Except for α and β chains, each of the regions has separate genes, and respective locus gets a figure equivalent to the observed antigen (e.g., HLA-DQB1). It describes molecular biology (e.g., HLA-DQB1 *) as the process. First two digits-serological typification of the antigen

• Third and fourth - denominations of the specific alleles

• Fifth and sixth-synonym variations

• Seventh and eighth- variations at introns 5’ or 3’ of the gene (Marsh et al., 2010).

The HLA Class I alleles obey the same rules except that letters ‘A’ or ‘B’ are not included to signify the chains’ polymorphism (e.g., HLA-A*0201). At the end of the allele denomination (e.g., HLAA*0104N), in which the gene never code for a protein, the letter ‘N’ (nil) is added.

Immunogenetics and inherited multifactorial diseases and disorders

Immunogenetics is directed at covering the effects of HLA and non-HLA, highlighting autoimmune diseases, pathogens, and immune disorders on all sides.

A. HLA loci (Saghazadeh & Rezaei, 2019)

1. Autoimmune and inflammatory diseases: Rheumatoid arthritis, eczema, acute anterior uveitis, alopecia areata, IgA nephropathy, asthma, type 1 diabetes, systemic lupus erythematosus, generalized vitiligo, ankylosing spondylitis, primary biliary cirrhosis, psoriasis, collagenous colitis, bechct’s disease, celiac disease, vasculitis, Crohn’s disease, ulcerative colitis, granulomatosis with polyangiitis (Wegener granulomatosis), atopic dermatitis, dermatomyositis, and Graves’ disease.

2. Infectious diseases: Human immunodeficiency virus (HIV) set-point viral load, human papillomavirus (HPV) seropositivity, acquired immunodeficiency syndrome (AIDS) progression. HIV-1 control, hepatitis B, and C virus related hepatocellular carcinoma, hepatitis B-related liver cirrhosis, chronic hepatitis B infection and viral clearance, dengue shock syndrome, leprosy, M. tuberculosis infection, malaria, resistance to enteric fever, and visceral leishmaniasis.

3. Gastrointestinal diseases: Barrett’s esophagus

4. Neurological disorders: Parkinson’s disease (PD), myasthenia gravis (MG), spinocerebellar ataxia, juvenile myoclonic epilepsy, narcolepsy, and multiple sclerosis (Ms)

5. Psychiatric disorders: Schizophrenia (SCZ) and autism

6. Joint diseases: Knee osteoarthritis

7. Cancers of the nasopharynx, cervix, colorectum, lung, blood cells and bone marrow (lymphoid cancers)

8. Adverse drug reactions: Stevens-Johnson syndrome/toxic epidermal necrolysis (carbamazepine), agranulocytosis (clozapine), pancreatic (thiopurine) and liver injury (terbinafine, fenofibrate, ticlopidine, and pazopanib)

9. Vaccines response: Hepatitis B

10. Male infertility due to nonobstructive azoospermia

B. Non-HLA loci (Saghazadeh & Rezaei, 2019)

The involvement of loci on non-HLA genes in genetic predisposition of immune-mediated inflammatory diseases is described: (1) cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) (2) protein tyrosine phosphatase (PTPN22) (3) TNF-π genes. Therefore, patients undergoing hematopoietic stem cell transplantation from complemented sibling donors may experience acute GVHD, proving non-HLA components role in the production of the immunogenetic profile.

Immunogenetics and spectrum of immune disorders

The innate immune system recognizes the molecular pattern and serves as the foremost line of protection toward any foreign substance, that is, by involving pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and domain-like receptors (NLRs) for nucleotide-binding oligomerization and signal-transducing molecules, for example, interleukin-1 receptor-associated kinase 4. Thus, failure of this will causes weakening of the immune system and renders it vulnerable to several other contagious ailments (Hollenbach & Jorge, 2015).

Autoimmune diseases

Psoriasis

It is a widespread chronic inflammatory disorder, which causes tissue harm to the skin and can develop other systemic problems at the same time. The disorder shows clinical and histological characteristics, like sticky oval-shaped plates, elevated silver scales, dividing lines, and erythema. It contributes to an excessive accumulation of keratinocytes, and in most cases may induce cardiovascular, psychological, and joint problems with a persistent plaque. In Immune-mediated skin disease, innate and adaptive immunities takes part in psoriatic lesions initiation (Michalek, Loring, & John, 2017)

Stimulating skin-specific T-cell-mediated autoimmune reactions, epidermal growth factors, nerve growth factors, adhesion factors, chemokines, neuropeptides, and TCR are correlated with psoriasis. The Th1 pathway is over-stimulated and elevated levels of Th1 cytokines and chemokines, like IL-2, IL-12, and IFN-э in psoriatic plaques cases are determined. Although in psoriasis, T cells, NK cells, NK T cells, and neutrophils lead to cutaneous inflammation. Investigators (Harden, Krueger, & Bowcock, 2015; Lowes, Suárez-Fariñas, & Krueger, 2014) noticed that Th1 and Th22 cells develop excess psoriatic cytokines (IL-17, IFN-g, TNF, and IL-22) that are responsible for facilitating potentiation of keratinocytes on psoriatic inflammation. While IL-23, TNF, and IL-17 play a major role in psoriasis catalog pathophysiology, over 60 loci are referred to as risk factors for rheumatoid arthritis.

HLA and non-HLA hereditary loci are linked commonly with psoriasis. NF-KB is a crucial regulating agent implicated in diverse intestinal immunoregulatory and inflammatory pathways, cell proliferation, differentiation, and apoptosis (Wang et al., 2017). It was noticed that the epidermal differentiation complex in the PSORS4 locus comprises of chromosome 1q21 genes, which are proliferating during keratinization mechanism (Zhang et al., 2009). Any irregularity in genes expression leads to intervention at specific stages of keratinocyte differentiation and eventually contribute to epidermal barrier dysfunction (Stawczyk-Macieja, Szczerkowska-Dobosz, R˛ebała, & Purzycka-Bohdan, 2015).

Rheumatoid arthritis

A synovial joint condition leading to persistent symptoms of synovial hyperplasia, autoantibody development like rheumatoid factor and anti-citrullinated protein antibody (ACPA), bone deformity, and systemic manifestations. The latter contributes to the stimulation of cells such as macrophages, monocytes, fibroblasts, and T cells, functioning as a cytokine orchestra, for example, IL-1, IL-6, and TNF-5–007, and is crucial to the dysfunctional transduction of the signal accompanying this inflammatory arthritis. In this disorder, a typical amino acid sequence in the HLA-DRB1 region is allied with the MHC class II gene, for example, HLADRB1* 0404 and DRB1* 0401. In ACPA-positive individuals, the non-HLA genetic loci are correlated with RA (Messemaker, Huizinga, & Kurreeman, 2015). RA-associated genes contributes in the nuclear factor-κB (NF-κB)-dependent signaling, TCR signaling, and JAK-STAT signaling.

Stastny (1976) states HLA-Dr4 is linked with RA, while Gregersen, Silver, and Winchester (1987) suggested a mutual epitope (SE) theory developed on the finding of RA-associated DRB1 alleles encoding similar amino acid sequence. Numerous SE-positive (SE+) DRB1 alleles were linked with RA and comprise the Dr4 subtypes- DRB1*0401, *0404, *0405, and *0408 and the DRB1*0101, *1402, and *1001 alleles. Nepom, Hansen, and Nepom (1987) has abridged the comparative risk assessments for most three recurrent SE+DRB1 alleles in the Caucasian population.

Autoimmune thyroid diseases

Lymphocytic thyroid infiltration with autoantibodies attacking thyroid antigens, like thyroid peroxidase (primarily in HT), thyroglobulin (Tg), and thyroid-stimulating hormone receptor, is described by AITDs such as Graves’ disease and Hashimoto’s thyroiditis (Gittoes & Franklyn, 1998; Pearce, Farwell, & Braverman, 2003). Genetic loci associated with AITDs are genetically distinct and are correlated with thyroid activity within the immune-modulating and HLA genes. Thus, leads to peripheral immunity, T-lymphocyte activation, and antigen presentation, and by interference with central and peripheral immunity, APCs, and eventual T cells activation, and immunogenetic susceptibility function to AITDs are well preserved. Gradually, data collection from various reports offered compelling support for two susceptibility loci for AITD; HLA and CTLA-4 (Vaidya et al., 2003; Yanagawa, Hidaka, Guimaraes, Soliman, & DeGroot, 1995). The HLA region on 6p21 was predisposed to autoimmune disorders (Cudworth & Woodrow, 1975), while earlier experiments gave inconclusive proof of GD interaction (Farid, Stone, & Johnson, 1980). Nevertheless, some findings ultimately offered reasonable proof that alleles were closely correlated with GD within the HLA class II region (Chen et al., 1999; Heward et al., 1998). The significant association signals for genes within the HLA class I region, HLA-C, and HLA-B, and the HLA class II region genes DRB1 and DQA1 have since been distinguished by advanced studies (Ban et al., 2004; Simmonds et al., 2005).

Primary biliary cirrhosis

A long-lasting liver cholestatic disorder described by the gradual degradation of small to medium-sized intrahepatic bile ducts progressing to cirrhosis and finally mortality or liver transplantation (Invernizzi, 2011) with the existence of the antimitochondrial antibody (AMA). PBC’s pathogenesis is autoimmune (Gershwin & Mackay, 2008), specified by precise serum and cell-mediated responses toward well-defined epitopes of self-antigens. It leads to the penetration of CD4+ T cells and CD8+ T cells-specific to AMA, that augmented in the patients liver with PBS. In addition, there is a stimulation of T cells, and other immune cells like B cells, macrophages, eosinophils, and NK cells contributing in the portal inflammation composition.

HLA variants that appeared defensive against PBC were identified by genetic tests. PBC-associated non-HLA loci primarily involve T cell-related genes. IL-2 receptor alpha deleted (IL-2Ralpha−/−), transforming growth factor-beta receptor II dominant-negative (dnTGFbetaRII), scurfy, nonobese diabetic c3c4, and AE2 gene-disrupted (AE2a, b−/−) identified in laboratory mice is genetically determined PBC models. For one of these, a PBC-like disease identified in a child with IL-2 alpha receptor (CD25) deficiency was IL-2 receptor alpha deleted (Aoki et al., 2006). They especially correspond to IL-12-JAK-STAT4, CD80/CD86, and IL7R-alpha/CD127, that helps in Th1 T-cell polarization, TCR signaling, and T-cell homeostasis. In the largest ever recorded PBC sequence of HLA polymorphisms (Invernizzi, Selmi, Mackay, Podda, & Gershwin, 2005). They provided evidence that PBC liability is related with the HLA DRB1*08 allele and DRB1*11 and DRB1*13 gives defense against the disorders. Hence other PBC-associated non-HLA loci are relevant to B-cell activity, TNF signaling, and NF-βB signaling.

Type 1 diabetes mellitus

T1DM is a T-cell-mediated autoimmune disease where insulin is functionally deficient as the immune system, marked by autoantibodies against islet cells, kills the β-cells in the pancreas (Eisenbarth, 2010). To improve the occurrence of T1DM and associated microvascular and macrovascular consequences, a collaborative endeavor was designed to identify further reliable preventative measures and novel therapeutic priorities.

It is a polygenic disease where almost half of the hereditary susceptibility to T1DM is accounted for by the HLA class II genes. Such genes possess loci that have been related to T1DM protection, and a variable number of tandem mini-satellite repeats and CTLA- are the non-HLA genes (Matzaraki, 2017). The function of HLA region genes in contrast to HLA Dr-DQ in T1D was first confirmed by the use of pretentious sib pairs with homozygous parents for Dr3 haplotype (Robinson, Barbosa, Rich, & Thomson, 1993). However, genetic heterogeneity was firmly confirmed by the observation that the serological relations at the DRB1 locus of HLA class II Dr3 and Dr4 displayed an elevated risk for heterozygotes of Dr3/Dr4 (Thomson et al., 1988). The variability of T1D genetics, however, is higher than expected in early studies. ‘HLA’ does not relate to a particular genetic locus, however, to a genome region which contains genes encoding three classical HLA class II and three classical class I antigens and a variety of extra genes whose susceptibility is mediated by-products.

Systemic lupus erythematosus

Systemic lupus erythematosus is a progressive inflammatory condition influencing the skin, heart, blood, muscle and joints, kidneys, and lungs of multiple organ systems. It stimulates the innate immune response and type I interferon activity, and autoantibodies prefer SLE’s pathogenicity. Immune complex clearance pathways such as apoptosis, neutrophil extracellular traps (NET), and nucleic acid-sensing are, however, dysfunctional. It requires the involvement of HLA and non-HLA genes. Several HLA genes were attached with SLE sensitivity and with the autoantibody profile (anti-dsDNA, anti-Ro, and anti-La) in SLE patients, comprising HLA-DRB1, HLA-DQB2, HLA-DQA2, and HLA-Dr3 (Hamilton et al., 1988). Interferon regulatory factors, STAT4, IFIH1, and osteopontin encoding genes pay to polygenic high IFN signatures. At the same time, it is known that TREX1, STING, SAMHD1, and TRAP necessarily lead to monogenic high SLE IFN signatures. Monogenic SLE derives from mutation(s) in genes relates to the mechanism of classical complement, apoptosis, and development of antinucleosome antibodies. TNFAIP3, TNIP1, BLK, ETS1, PRDM1, and IKZF1 are SLE-associated genes within regulatory regions (e.g., exons, splice sites, introns, and intergenic sites). Lastly, SNPs are associated with SLE within the coding region of genes PTPN22 and immunoglobulin-like transcript 3 receptor (Morris et al., 2012).

Systemic sclerosis

The clinically assorted connective tissue disease with diverse etiology is SSc. Significant advancements were made in understanding the genetic history of SSc in the development of large-scale genetic experiments, such as genome-wide interaction studies (GWASs) or the Immunochip network. SSc is s a multisystem disorder distinguished by a heterogeneous clinical symptom framework varying from confined to dispersed cutaneous SSc and recurrent skin and internal organ fibrosis (Charles, 2006). SSc-associated non-HLA genes are considered to have a significant part in innate immunity, interferon signature and inflammation, adaptive immune responses, B and T-cell proliferation, survival and production of cytokines, apoptosis, autophagia, and fibrosis.

The perivascular infiltrates of mononuclear inflammatory cells characterize the inflammation in earlier scleroderma skin biopsies (Fleischmajer, Perlish, & Ducan, 1983). However, people having SSc have enhanced circulating cytokine levels with distinctive trends based on SSc-associated autoantibodies and dysregulation of type I interferon pathways close to systemic lupus erythematosus (Gourh et al., 2009b). The existence of non-overlapping SSc-associated autoantibodies [e.g., anti-topoisomerase I, anti-centromere, and anti-RNA polymerase III (Arnett, 2006)] is ideally illustrated by autoimmunity.

Neurological diseases

A compromised central nervous system (CNS) and peripheral nervous system (PNS) are anxious with neurological disorders. Neurological disorders account for 7.1% of the global incidence of illness, estimated in disability-adjusted years of existence across both causes and ages (Chin & Vora, 2014). In the case of many neurological diseases, genes encoding antigen-presenting molecules inside the human MHC contribute to the maximum hereditary risk factor.

Multiple sclerosis

Ms is the neurological ailment specifically and frequently linked with variance in the HLA area. The pathological features of Ms are demyelinating lesions, frequently described based on whether or not autoimmune progressions entail demyelination. It is a persistent autoimmune condition, mainly characterized by the stimulation of CD4+ self-reactive T cells and the polarization of Th1 T cells, followed by the development of antibodies, CD8+ T cells destroying the CNS tissues (Jersild et al., 1973). CD4+ T cells expressing KIRs are engaged in antibody development, and NK cells expressing KIRs trigger antiviral and antitumor innate immune reactions. Hence, KIR polymorphisms may influence the individual’s risk of Ms due to their effect on antiviral immunity and antibody formation (Hollenbach & Jorge, 2015). The very first proof of the interaction of HLA class I antigens with Ms was available in 1972 (Naito, Namerow, Mickey, & Terasaki, 1972), with an Ms risk, initially stated to be concomitant with HLA-A*03 and HLA-B*0729 (Compston, Batchelor, & McDonald, 1976) relying on their serological specificity.

Parkinson’s disease

PD is a too prominent and progressively compromised neurodegenerative condition, which comprises a spectrum of neurological, epidemiological, and genetic subtypes (Espay, Brundin, & Lang, 2017). This contributes to neurodegenerative phenotype; local neuroinflammation is a characteristic of PD and stimulates the production of microglia and astrocytes and the subsequent activation of major class II (MHC-II) histocompatibility molecules. Inflammatory signaling in PD is not limited solely to the brain but also concerns the peripheral immune system, for example, enhanced expression of inflammatory molecules in the central (Mogi et al., 1994) and PNS (Qin, Zhang, Cao, Loh, & Cheng,