HLA typing in organ transplant part 1

The transplant of organs and tissues is one of the greatest curative achievements of this century. In organ transplantation, the adaptive immunity is considered the main response exerted to the transplanted tissue, since the main goal of the immune responses is the major histocompatibility complex molecules expressed on the surface of donor cells. Cell surface molecules that induce an antigenic stimulus cause the rejection immune response to grafted tissue or organ. A wide variety of transplantation antigens have been described, including the major histocompatibility molecules, minor histocompatibility antigens, ABO blood group antigens and endothelial cell antigens. The sensitization to major histocompatibility complex antigens may caused by transfusions, pregnancy, or failed previous graft leading to development of anti human leucocyte antigen (HLA) antibodies that are important factor responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complication anti-HLA Abs  may be present  in healthy individuals. Methods for HLA typing are described, including serological methods, molecular techniques of sequence-specific priming, sequence-specific oligonucleotide probing, sequence based typing and reference strand-based conformation analysis method. Problem with organ transplantation are reservoir of organs and immune suppressive treatments that used to decrease rate of rejection with less side effect and complication

Human Leukocyte Antigen (HLA) part 122

Most of the genes in the major histocompatibility complex region express high polymorphism that is fundamental for their function. The most important function of HLA molecule is in the induction and regulation of immune responses. Many of human diseases, such as autoimmune, inflammatory and malignant, are significantly  more common among individuals carrying particular HLA alleles. HLA-disease association is the name of this phenomenon, and mechanism underlying is still a subject of hot debate.

Human Leukocyte Antigen (HLA) part 121

Most of the genes in the major histocompatibility complex region express extremely high intrapopulational polymorphism. Such polymorphism in virtually all vertebrates can hardly be interpreted  as an incidental phenomenon, and dozens of theories have attempted to elucidate the evolutionary pressures that have shaped it.  First, the polymorphism is maintained by heterozygote advantage. As HLA gene expression is co-dominant, HLA heterozygotes express absolutely more types  of functional HLA proteins than homozygotes and are thus able to present a broader spectrum of peptides. Second, the HLA polymorphism is a result of frequency-dependent selection in an evolutionary arm race between pathogens and the vertebrate immune system. According to this scenario, pathogens rapidly evolve the ability to escape recognition of most common host genotypes, for example by mutation  that eliminates all peptides which affinities to common variants of the host HLA genes. Third, the maintenance of HLA polymorphism under variable selection over time due to a varying degree of pathogen presence. It shows that temporal variation inresistance itself can  maintain polymorphysm even without co-dominant-based heterozygote advantage. Finally, the HLA polymorphism is maintained by sexual selection. Individuals of one or both sexes prefer partners possessing  a relatively dissimilar partners increases offspring heterozygosity at the HLA  and therefore can potentially increase pathogen resistance in resulting progeny.

Human Leukocyte Antigen (HLA) part 120

HLA AND SOCIAL BEHAVIOUR

Mate choice studies on rodents and other species usually find preference for HLA dissimilarity in potential partners. HLA-associated mate choice studies in humans are based on three broadly different aspects:

• Odour preferences
• Facial preferences
• Actual mate choice surveys

As in animal studies, most odour-based studies demonstrate disassortative preferences, although there is variation in the strength and nature of the effects. In contrast, facial attractiveness research indicates  a preference for HLA-similar individuals. Results concerning HLA in actual couples show  a bias towards similarity in one study, dissimilarity in two studies and random distribution in several other studies.

Human Leukocyte Antigen (HLA) part 119

HLA AND LONGEVITY

Literature data suggest that human longevity may be directly correlated with optimal functioning of the immune system. Therefore, it is likely that one of the genetic determinants  of longevity resides in those polymorphysms for the immune system genes that regulate immune response. Accordingly, studies performed  on mice have suggested that the HLA, known to control  a variety of immune functions, is associated with the lifespan of the strains. In the last 25 years, a fair number of cross-sectional studies that searched for the role of HLA genes on human longevity by comparing HLA antigen frequencies between groups of young and  elderly persons have been published, but conflicting findings have been obtained. In fact, the same HLA antigens are increased in some studies decreased or unchanged in others. On the whole that could lead to hypothesize that the observed age-related differences in the frequency of HLA antigens are due to bias. The hypothesisis real for most studies owing to major methodological problems. However, some studies that do not meet these biases have shown an  association between longevity and some HLA-DR alleles or HLA-B8, DR3 haplotype, known to be involved  in the antigen non-specific control of immune response. Thus, HLA studies in human may be interpreted to support suggestions derived from the studies  on congenic mice on HLA effects on longevity. However, in mice, the association may be by way of susceptibility to lymphomas whereas, in human beings, the effect on longevity is likely, via infectious disease susceptibility. Longevity is associated with positive or negative selection of alleles  (or haplotypes) that, respectively, confer resistance or susceptibility to diseases, via peptide presentation or via antigen non-specific control of the immune response.

Human Leukocyte Antigen (HLA) part 118

Several hypotheses have been suggested to explain how variation in HLA class I genes could trigger autoimmunity. HLA class I molecules play a role in presenting endogenous antigens, including those derived from viruses and/or bacteria, which have been proposed to be key enviromental trigger for autoimmune disease. Viral/bacteria antigens may trigger autoimmun disease through molecular mimicry and via acting as superantigens HLA class I molecules  could also be associated with autoimmune disease due to their role in inhibiting natural killer cell activity. Non-viral mechanism have also been proposed including:

• Protein misfolding causing specific molecules to accumulate in the RER, where they are degraded, potentially causing a pro-inflammatory unfolded protein stress response or misfolded proteins themselves to become autoantigenic
• Conversion of HLA class I molecules into peptides which could then be presented by HLA class II molecules to the immune system and an immune respones mounted as has been pr0posed in ankylosing spondylitis with B*27
• Peptide binding and presentation by specific HLA molecules as suggested earlier for HLA class II molecules with mechanisms including selection of antigen-specific CD8 T cells during thymic education, and positive or negative selection of a strong CD8 T suppressor population

Human Leukocyte Antigen (HLA) part 117

Ankylosing spondylitis  is a complex disease involving multiple risk factors, both genetic and environtmental. Ankylosing spondylitis patients are predominantly  young men, and the disease is characterized by inflammation  and ankylosis, mainly at the cartilage bone interface and enthesis. HLA-B27 has been known to be the major ankylosing spondylitis susceptibility gene for more than 40 years and is present in over 90% of ankylosing patients. There are about HLA-B*2731 alleles with the B*2701,B*2704 and *2705 alleles are strongly associated with susceptibility, and B*2706 and B*2709 alleles are associated with protection. The presence of amino acid Aspartate or Histidine at position 116 is the only difference between B*2705 and B*2709. There are three principle to distinguish it from other HLA class I molecules such as  the peptide-binding specifity, the tendency to misfold and the predilection  for forming heavy chain homodimers during cell-surface recycling. The current hypotheses linking HLA-B27 to spondyloarthritis pathogenesis includes:

• Arthritogenic peptides, self peptide selected and presented by properly folded forms of HLA-B27 complexed with β2 m have been  hypothethesized to be the target of autoreactive CD8 T cells and serve as an upstream initiator of inflammation
• Recognitizion of non-canonical HLA-B27, naturally occuring self-surface HLA-B27 dimers are hypothesized  to be recognized by killer immunoglobulin receptors (such as KIR3DL2) in the leucocyte immunoglobulin like receptor family and trigger inflammation
• HLA-B27 misfolding, the formation of misfolded oligomers and BiP binding by newly synthesized HLA-B27 heavy chains causes ER stress, which has intrinsic effects on cellular function that are hypothesized to promote development of spondyloarthritis.

HLA-B27 can exhibit all three of these behaviours in the same cell and these concepts are not mutually exclusive.

Human Leukocyte Antigen (HLA) part 116

Several non-mutually exclusive mechanisms have been proposed to explain association of  DR/DQ with autoimmune diseases.

• Variation in binding groves of associated DR/DQ molecules could lead to preferential presentation of only a specific limited set of self-peptides or low affinity self-peptides may allow autoreactive  T cells to escape  tolerance and enter the periphery. This could affect  thymic T cell education, causing incomplete thymic tolerance  and a Th and Treg  cell population that does not recognize all self-molecules
• Polymorphic residues of the T cell receptor-exposed  surfaces  of DR/DQ could select autoreactive T cells  or fail to select a good Treg population
• Promiscuous restriction where some T cell receptor will use a series  of different restriction  elements to bind  to and, therefore, interact with a wider  variety  of different peptides
• Preferential binding in DR/DQ heterozygous  subjects could be occuring through epitope stealing by one HLA molecule over another which depending on T cell receptor  restriction of CD4 Th cells, could affect whether an immune response is mounted
• Presentation of endogenous antigens by HLA class II. Although class II molecules traditionally present exogenous antigens and class I present endogenous antigens, this system is not absolute and presentation of endogenous antigens by class II and exogenous antigen by class I  can be seen. This could alter how these antigens  are presented to the immune system and the response triggered. These hypothesis suggest a series of potential mechanistic pathways by which the HLA class II molecules could be involved in disease onset by altering the Th and Treg cell repertoire or through changes in how the antigen is recognized in the periphery

Human Leukocyte Antigen (HLA) part 115

Multiple sclerosis is a chronic disabling disease of the central nervous system that results from the effects of unknown enviromental risk factors acting in genetically  susceptible individuals. Susceptibility in multiple sclerosis been linked mainly to the HLA-DRB1 locus, with the HLA-DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602-DRB5*0101) dominating  multiple sclerosis risk in Caucasians. Although genes in the HLA-II regions, particularly DRB1*1501, DQA1*0102-DQB1*0602, are tight in linkage disequilibrium and gene, candidate studies identified the DRB1*1501 allele as the primary risk factor in multiple sclerosis. Many genetic and immune-functional studies have indicated DRB1*1501 as a primary risk factor in multiple sclerosis, while only some functional studies suggested a disease-modifying role for the DRB5*01 or DQB1*06 alleles.

Human Leukocyte Antigen (HLA) part 114

An immense number of studies based on different ethnicities  have identified HLA class II associations with systemic lupus erythematosus especially the haplotypes containing DR2 and/or DR3 are directly involved in disease pathogenesis, clinical presentation, lupus nephritis and production and specificity of autoantibodies. Studies in European  populations identified a potential association of the class II HLA-DRB1 alleles HLA-DRB1*0801, -*0301 and -*1501 with systemic lupus erythematosus. Two of these alleles (HLA-DRB1*0301 and -*1501) have also been identified in a recent study  of the IMAGEN consortioum  using high-density SNP typing across the major histocompatibility complex and in other populations.

Human Leukocyte Antigen (HLA) part 113

The mechanism underlying the effect of the shared epitope is unclear, but it was postulated that the presentation of arthritogenic self-peptides, molecular mimicry  with foreign antigens or T cell repertoire selection are involved. While these hypotheses are all plausible, they are difficult to reconcile with the fact that data supporting antigen-specific responses as the primary event in reumathoid arthritis are inconclusive. Additionally, several other human disease have also been shown to be associated with shared epitope encoding DRB1 alleles such as type I diabetes, systemic lupus erythemathosus and autoimmune hepatitis.

Human Leukocyte Antigen (HLA) part 112

The term "shared epitope" most commonly refers to a five amino acid sequence motif in residues 70-74 of the DR chain coded by several HLA-DRB1 alleles that are overpresented among patients with remathoid arthritis. The shared epitope motif consists of three homologous amino acid sequence variants.

• QKRAA, the shared epitope variant that is the most common  motif among Caucasian is coded primarily  by the HLA-DRB1*0401 allele
• The second most common motif, QRRAA, is coded by several alleles, among them HLA DRB1*0404, DLA-DRB1*0101 and HLA-DRB1*0405
• The third motif, RRRAA, coded by allele HLA-DRB1*1001, is the rarest

In addition to increasing remathoid arthritis risk, shared epitope coding  HLA-DRB1 alleles have been shown to associate with more severe  disease and to exhibit allele-dose effect, that is patients with two shared epitope coding alleles tend to experience more severe disease than patients with one allele, who, in turn, have more severe remathoid arthritis than  shared epitope-negative.

Human Leukocyte Antigen (HLA) part 111

A stronger association with the DQB1 locus alone was reported when an allele-encoding aspartic acid at position β57 of DQB1 was found to be associated with resistance to type I diabetes, while an allele encoding a neutral residue, such as alanine or serine at position β57 conferred susceptibility. This molecule forms a critical residue in peptide-binding pocket nine (P9) of the DQB1-binding pocket involved in antigen presentation and T cell receptor interaction. Its carboxylate group forms a salt bridge with arginine at position α57 of DQA1 chain that stabilizes the heterodimer between the DQA1 and DQB1 chains. The presence of aspartat at this position could alter the stability of the molecule and/or  antigen-presenting  repertoire, thus making the molecule more prone to binding autoreactive antigens.

Human Leukocyte Antigen (HLA) part 110

Although HLA-DR3/4 genotype confers extremely high risk, there is a spectrum of risk associated with HLA-DR/DQ genotype-from increased, to neutral, to protective. For instance, the HLA-DQA1*0102, DQB1*0602 haplotype  confers dominant protection from type 1 diabetes, even in the presence of islet autoantibodies. However, while the incidence of type 1 diabetes is increasing,  the percentage of patients carrying the high risk HLA-DR3/4 genotype is decreasing. These temporal changes in HLA genotypes  suggest increased environtmental pressure with higher disease progression rate in individuals with lower risk HLA genotypes and/or contribution of other non-HLA class II  alleles or non-HLA-related alleles to type I diabetes risk.

Human Leukocyte Antigen (HLA) part 109

Type I diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major type I diabetes susceptibility locus maps to the class II loci HLA-DRB1 and HLA-DQB1 on chromosome 6p21. The highest risk DR/DQ haplotypes for type I diabetes are DR3-DQA1*0501-DQB1*0201(DR3) AND DR4-DQA1*0301-DQB1*0302(DR4), and these alleles account for 30-50% of genetic type I diabetes risk. The association of specific HLA-DQB1 alleles and genotypes with type I diabetes susceptibility/protection depends on the ethnicity and racial background of each population. For example, in Caucasian, type I diabetes is positively associated with DQB1*0201 and DQB1*0302 while in Japanese, it is associated with DQB1*0401 and DQB1*0303

Human Leukocyte Antigen (HLA) part 108

HLA and autoimmune disease

Strong association between the HLA region and autoimmune disease has been established for over 50 years. Association of components of the HLA class II encoded HLA-DRB1-DQA1-DQB1 haplotype has been detected with several autoimmune diseases including reumathoid arthritis, type I diabetes and grave's disease. Molecules encoded by this region play a key role in exogenous antigen presentation to CD4 Th cells, indicating the importance of this pathway in autoimmune disease initiation and progression. Association of the HLA class I region, independent of known HLA class II effects, has now been detected for several autoimmune diseases, including strong association of HLA-B with type I diabetes and HLA-C with multiple sclerosis and grave's diseases. These results provide  further evidence  of a possible role for bacterial or viral infection and CD8 T cells in autoimmune disease onset.

Human Leukocyte Antigen (HLA) part 107

Several studies  have focused on the distribution of these two alleles in women experiencing  recurrent pregnancies loss. Expression of HLA-E at the feto-maternal interface may be implicated in the successful pregnancy  because of its ability to downregulate maternal immune response. In the decidua, the area of the interface where feto-maternal interaction occurs, CD-56-positive natural killers cells are the dominant type of lymphocytes and express CD94:NKG2A complex, suggesting that HLA-E protein on the trophoblasts can be recognized by the maternal immune system. Evidence showing lower expression of HLA-ER, and its lower stability may impair its capability to downregulate natural killer cells and hence may be associated with recurrent pregnancies loss.

Human Leukocyte Antigen (HLA) part 106

The HLA-E protein is one of the most extensively studied HLA class Ib antigens and the least polymorphic one compared  to other HLA class I molecules. In the human population, there have been reported just ten alleles encoding three different peptides. Only  two of these alleles  namely HLA-E*0101 and HLA-E*0103, are widely distributed (around 50% each). The proteins encoded by these alleles differ from each other in one amino acid at position 107. In HLA-E*0101, it is arginine, and in HLA-E*0103, it is glycine. The difference between these proteins manifest itself in surface expression levels, affinities to leader peptides and thermal stabilities of their complexes. The HLA-E molecule is a ligand for CD94/NKG2 receptors on natural killer cells and T cell receptor, so it plays a double role in both innate and adaptive immunity.

Human Leukocyte Antigen (HLA) part 105

HLA-G has many immune regulatory functions in pregnancy. First, HLA-G interact with the inhibitory receptors, immunoglobuline-like-transcript-2 and -4 (ILT-2 and ILT-4) expressed by a wide variety of immune cells especially monocytes, macrophages. The affinity of these receptors for HLA-G is higher than for other HLA class I molecules. In the same time, these receptors compete with CD8 in binding HLA-G, which could prevent  activation of cytotoxic CD8 T cells, thereby contributing  to the induction of tolerance. Furthermore, HLA-G has been shown to up regulate both ILT-2 and ILT-4, along with the killer-cell immunoglobulin-like receptor-2DL4 (KIR2DL4), on the surface of both antigen presenting cell, natural killer cells and CD4 T cells without preceding antigenic co-stimulation. This provides an interesting possibility that these receptors function at the materno-foetal interface by raising the treshold of the maternal immune system activation, thereby serving to induce tolerance.

Human Leukocyte Antigen (HLA) part 104

Lack of classical HLA antigens on trophoblast has been postulated as an argument against the hypothesis that foetal rejection is akin to allograft  rejection. However, downregulation of HLA-G molecules and increased expression of classical HLA antigens were documented in recurrent pregnancy loss and pre-eclampsia pregnancies. The sparce presence of anti-HLA antibodies in recurrent pregnancies loss patients resulted probably from the failure to carry gestation long enough to produce response. They could originate from recognition of classical HLA antigens expressed on small remnants of trophoblast and foetal membranes exposed to maternal effector cells "cleaning up"  uterine cavity post-delivery. Anti-HLA antibodies are not able to affect adversely the next pregnancy with the same partner, as classical HLA targets are hidden, and trophoblast exposed to maternal immune recognition is protected by HLA-G.

Human Leukocyte Antigen (HLA) part 103

For many years, the term "foetal allograft" has been widely used for description of foetal immunological status during pregnancy. In such approach, immunological acceptance describing maternal reaction directed towards foetal antigen is understood as the state of recipient's tolerance to an engrafted organ. Consequently, immunopathological recognition of foetal antigens that occurs in recurrent pregnancy loss or recurrent misscarriage and posibly pre-eclampsia should be viewed as graft-rejection like alloimmune reaction. However, there are still some doubts concerning this approach, as some proofs speak against it. For example, absence of expression of classical HLA antigens on the surface of trophoblast, foetal survival is not affected by the HLA-sharing between partners and  no impact on the pregnancy outcome for the blocking-anti-HLA. Recurrent pregnancy loss is though to be due to increased activity of the innate immune system (especially natural killer cells) and organ specific auto-immunity as indicated by a higher prevalence of autoantibodies and its association with particular maternal class II HLA genotypes especially HLA-DR.

Human Leukocyte Antigen (HLA) part 102

The discovery that foetal cells are devoid of the highly polymorphic HLA class Ia molecules, except for a low expression of HLA-C, is believed  to play a dominant role for the induction of tolerance to the semi-allogenic foetus. Interestingly, the foetal-derived tissue in placenta does express the loss polymorphic HLA class Ib molecules, HLA-E, HLA-F and HLA-G, which has led to increased interest in the immunological role of these three proteins during pregnancy

Human Leukocyte Antigen (HLA) part 101

HLA and pregnancy problems

Cases of recurrent abortions, pre-eclampsia or babies born with hemolytic diseases of the new born raise a questiion  "Why did your mother reject you?" Although, after looking at the complexity  of the maternal-foetal immune interactions and the cases of successful pregnancies, with surprise and admiration to the question now becomes "Why didn't your mother reject you?" The cells from the placenta are the only part of the foetus that interacts directly with the mother's uterine cells, and therefore, the maternal immune system is able to evade immune rejection. The foetus itself has no direct contact with maternal cells. Moreover, the foetus per se is known to express paternal HLA antigens and is rejected as allograft if removed from its cocoon of trophoblast and transplanted to the tight muscle or kidney capsule of the mother. A number of mechanisms have been proposed  to account for the immune-privileged state of the decidua. The different hypothesis can be summarized in the five main ideas:

• A mechanical barrier effects of the trophoblast
• Suppression of the maternal immune system during pregnancy
• The absence of HLA class I molecules in the trophoblast
• Cytokine shift and more recently
• Local immune suppression mediated by the Fas/FaL system

Human Leukocyte Antigen (HLA) part 100

The role of the HLA in drug allergy has received particular attention with regard to certain drugs and ethnic groups. The drug hypersensitivity syndrome caused by abacavir is strongly associated with HLA-B*5701, and key structures in the peptide-binding cleft of HLA-B*5701 have been identified that permit non-covalent interaction with this drug. This binding may also occur in so-called empty, non-peptide bearing major histocompatibility complex class I molecules. The binding of abacavir to the F pocket of HLA-B*5701 alters the spectrum of self-peptides that can be presented by this major histocompatibility complex class I molecule. This results in the display of a novel peptide repertoire that appears foreign to the immune system. Memory T cell responses in abacavir-hypersensitive donors are directed against a self-peptide that requires abacavir to efficiently bind to HLA-B*5701. This situation is then analogous  to alloreactions with the development of a severe cytotoxic response through the activation of cross-reactive effector memory cytotoxic T cells. The rapidity of onset of the reaction and its intensity may depend upon differences in T cell receptor validity.

Human Leukocyte Antigen (HLA) part 99

However,  not all drugs seem to capable of interacting covalently with proteins, and some immune reactions to drugs occur without antigen processing. This has to led the pharmacological interaction or p-i hypothesis, whereby some chemically inert drugs are able to bind non-covalently to antigen-presenting structures such as the T cell receptors or HLA and cause stimulation directly of an immune  response, as is the case with sulfamethoxazole. Most drugs have been designed to fit into protein pockets in receptors and enzymes. The drugs interaction with the receptors is highly specific such that small changes in drug structure can affect reactivity. T cell activation can occur rapidly, before metabolism and processing  of the drug could occur. However, the reactions that occur are the same as those induced by a drug-modified peptide antigen, because the immune response once activated proceeds in a fixed way. The hypothesis could explain why reactions can sometimes occur without known previous sensitization.

Human Leukocyte Antigen (HLA) part 98

The drug or a reactive product reacts with a self-protein or peptide which results in formation of a novel drug conjugate or adduct. This undergoes antigen processing to generate a small, but novel HLA ligand that is loaded onto the HLA and transported to the cell surface, where it can interact with antigen-specific T cells. This process requires a metabilically active antigen presenting cell and time. once generated, the HLA drug-peptide complex is stable and ligand removal requires peptide exchange or peptide stripping from tha HLA groove.

Human Leukocyte Antigen (HLA) part 97

Because most drugs are low molecular weight chemicals, in theory too small to be able to stimulate  the immune system, it has long been assumed that the drug or a reactive metabolite must first bind  covalently to a macromolecule such as a protein, forming a multivalent conjugate that is processed and presented by the immune system to T cells. Probably, the clearest example of drug haptenation is that which occurs with penicilline, which is chemically reactive and undergoes stable covalent binding to proteins or peptides, resulting in the creation of an immunogenic self protein.

Human Leukocyte Antigen (HLA) part 96

HLA and sensitivity

Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. Several alternative mechanisms of immune recognition have been proposed to explain HLA-associated  drug hypersensitivity. These mechanisms include the hapten (or pro-hapten) concept, which states that drugs and their metabolites are too small to be immunogenic on their own, but act as haptens to modify certain self-proteins in the host that lead to immune recognition of the resulting hapten: self-peptide complexes as de novo antigens. The super antigen interaction concept states that drugs  may bridge T cell receptor and HLA molecules without binding directly to peptide antigen. The p-i concept  (short for pharmacological interaction with immune receptors) states that drugs can induce the formation of HLA-drug complexes that can activate T-cell immune responses directly  without requiring a specific peptide ligand. Recently, several groups  reported data suggested that these commonly considered mechanisms mentioned above may not apply in the case of abacavir. Instead, abacavir seems to alter the peptide repertoire presented by HLA-B*57:01 by occupying sites within the antigen-binding cleft. The polymorphic residues implicated in drug interactions suggest that different drugs may bind HLA molecules or other elements of the trimolecules complex (HLA, peptide and T cell receptor) in alternative binding modes.

Human Leukocyte Antigen (HLA) part 95

In addition to the classical HLA-A, HLA-B and HLA-DR antigens, the role of HLA-C and HLA-DQ  antigens in terms of graft survival or sensitization is now documented.  Analysis of the immunogenicity of incompatible HLA-A, HLA-B antigens  in terms of the numbers of amino acid residue mismatches (epitope mismatches) is associated  with better transplant outcome than conventional matching based on HLA typing by serology. Although anti-DP antibodies are frequently detected in sensitized  patients, their impact on transplant outcome is still not clear and needs to be further evaluated. In the context of kidney transplantation from live donors, donor age and HLA matching have recently been shown to be independent donor-related risk factors associated with both decreased patient and graft survival

Human Leukocyte Antigen (HLA) part 94

However, the results of Opelz and Dohler on a large study cohort (135.970 kidneys transplants) clearly showed that the significance of HLA matching on graft survival rate has not lost its importance, and this is obvious when comparing the decades  1985-1994 and 1995-2004. Even when analysing the last five years  of the study period separately  (2000-2004), a significant correlation of graft survival with HLA matching was disclosed. An analysis of the scientific Registry of transplant recipients database (1988-2007) consisting of > 15.000 re-transplant candidates revealed the negative effect  of poor HLA matching on graft survival after the first  transplantation and was associated with a significant increase in the development of anti-HLA antibodies measured by panel reactive  antibody proportional to  increasing HLA mismatches. Only 10% of patients with zero HLA-A and HLA-B mismatches became newly sensitized after graft loss compared to 37% (>30%  panel reactive antibody) in transplants with a greater extent of HLA mismatches.

Human Leukocyte Antigen (HLA) part 93

RENAL TRANSPLANTATION

Although the impact of HLA compatibility has been recognized for two decades, the advances in immunosuppression protocols are such that rejection episodes are managed more efficiently, thus minimizing the importance of HLA matching. A study based  on the United Network for Organ Sharing data reported that the impact of HLA compatibility had greatly diminished. Consequently, some allocation programs have gradually toned down the role of HLA matching from the algorithms used for prioritizations on the waiting list. The lower importance of HLA matching was also favoured in the early years of the 21th century with the advent of the microarray-based luminex technology for detecting donor-specific antibodies, thus allowing organ allocation around well characterized HLA specifities.

Human Leukocyte Antigen (HLA) part 92

While the role of donor-specific antibodies in solid organ transplantation is well established, their importance in hematopoietic stem cell transplantation is only now becoming clear. A review of the literature reporting on HLA immunization in hematopoietic stem cell transplantation provides ample circumstantial evidence that donor-specific antibodies are associated with a twofold to tenfold increase of graft failure of HLA-mismatched hematopoietic stem cell transplantation, irrespective the type of the graft or the patient conditioning. Hematopoietic stem cell transplantation with HLA-mismatched donors is for many patients the only curative option. Relapse of malignancy, graft versus host  disease and post-transplant  infection still poses considerable hurdles for transplant success. The contribution HLA antibodies to transplant outcome have been a relatively neglected focus until recently. However, not all HLA antibodies can cause graft failure which may depend  on antigens involved, titre or other, as yet unravelled, functional antibody potentials. A higher number of stem cells may  overcome rejection in the case of low strength antibodies, but it is impossible to give more specific recommendations. Even less can be concluded from approaches to reduce donor-specific antibodies. It seems reasonable to aim for a negative or low titre donor-specific antibodies at the moment of hematopoietic stem cell administration and to inhibit antibody-mediated cell destruction machinery by blocking the macrophage. Although the role of donor-specific antibodies  in graft failure is becoming acknowledged, non-donor-specific antibodies may also be a confounder in the search  for a broader repertoire of allo-antibodies affecting transplant outcome. It is obvious that progress cells for registration and collaboration to resolve confusion around test results. For this aim, the assessment of HLA antibodies should be included in hematopoietic stem cell transplantation management protocols.

Human Leukocyte Antigen (HLA) part 91

There are conflicting data concerning the value of selecting an allelic mismatch over an antigenic mismatch. Petersdorf et al did not find any apparent difference between allele and antigen mismatches with respect to the number of deaths from transplant, suggesting that donors with a single HLA allele antigen mismatch may be used for hematopoietic stem cell transplantation when a fully matched  unrelated donor is not available for patients with severe diseases not permitting time  for lengthy search. There were  no significant differences in survival depending on whether the mismatch was allelic or antigenic mismatch at HLA-C. However, Flomenberg et al found that antigenic mismatch was associated with higher mortality compared to allelic mismatch . They indicated that selection of donors with high-resolution mismatches over those with low-resolution mismatches may lower the rate of post transplant complication.

Human Leukocyte Antigen (HLA) part 90

HLA sequence polymorphisms that are recognized by antibodies (serologic method) are termed antigens, whereas those that can be identified only by DNA-based typing methods are termed alleles. Any given HLA antigen may be encoded by a family of HLA alleles with similar nucleotide sequences. Transplant donor and recipient pairs with different HLA antigens always have different alleles (antigen mismatched), and pairs with the same allele always have the same antigen (matched). Some donors and recipients with the same HLA antigen have different alleles  (alleles mismatched). With few exceptions, HLA alleles mismatched  are characterized by amino acid substitutions in the region of the HLA molecule that bind peptides for presentation to T cells, whereas HLA antigen mismatches are characterized by amino acid substitutions relevant to both peptide binding and contact with T cells.

Human Leukocyte Antigen (HLA) part 89

Petersdorf summarized the rich history of studies investigating the importance of HLA matching in haematopoietic stem cell tranplant either unrelated donor transplantation  or cord blood transplantation. In unrelated donor hematopoietic stem cells transplantation, there are five major concepts regarding the role of donor HLA mismatching and graft versus host disease :

• Type and match at high resolution
• Consider HLA-DP especially HLA-A, C, B, DR, DQ-mathced donors are available
• When matched donors are not available, limit the total number of HLA mismatches
• When selecting among HLA-mismatched donors, distinguish allele from antigen mismatches
• Consider KIR ligands, KIR alleles, and KIR haplotypes

In cord blood transplantation, there is strong evidence that fewer  mismatches are associated with overall improved outcome and that HLA-associated effects are influenced by the cell dose of the cord blood unit. Like unrelated donor hamatopoeitic stem cell transplantation, there is emerging evidence that matching the cord blood unit for HLA-C will lower post-transplant complication.

Human Leukocyte Antigen (HLA) part 88

After 1998, when better HLA typing  methods replaced DNA fingerprinting, serology and low resolution methods used for final donor matching the overall survival of transplant patients have improved greatly. Most studies now agree that HLA-DQB1 does not need to be considered  in a well-matched donor, but there is evidence that there may be additive effects of a DQB1 mismatch, if a mistmatch at another locus is present. In certain circumstances (and particularly if more than one donor is available), typing for the HLA-DPB1 locus should be performed and the degree and the type of matching considered in donor selection.

Human Leukocyte Antigen (HLA) part 87

HAEMATOPOIETIC  STEM CELL TRANSPLANT

The HLA system is the primary immunologic barrier to successful stem cell transplant. Therefore, the clinical outcomes of haematopoietic stem cell transplant are dependent on optimizing the histocompatibility matching between the patient and the donor. The HLA antigens are effectve  stimulators and targets of graft versus host disease and graft rejection. HLA possess outstanding  ability to elicit immune response either by presentation of variable peptides or by recognition of polymorphic fragments of  foreign HLA molecules. In the future,  evaluation before haematopoietic stem cell transplant is likely to comprise a more detailed genetic analysis of patient and donor, but currently the standars is HLA typing at A, B, C, DRB1 and DQB1 genetic loci.

Human Leukocyte Antigen (HLA) part 86

HLA and transplantation

In addition to situations in which a malfunction of the HLA system occurs, problems can arise when it functions too well. This is the case when one attempts to transplant tissues or organ between genetically disparate individuals of the same  or different species (allografts and xenografts, respectively). The T cell receptors of the recipient's lympocytes recognize either the donor's (allogeneic) HLA molecules on the antigen presenting cell of the graft  (a process known as direct presentation) or the donor's HLA molecules on antigen presenting cell of the recipient (a process known as indirect presentation). During indirect presentation, the peptides are generated by degradation of the allogeneic HLA molecules released from the graft,

Human Leukocyte Antigen (HLA) part 85

The HLA-B8, DR3 haplotype is remarkable for its association with a number of autoimmune diseases such as lupus,  type I diabetes mellitus and IgA deficiency. The extended HLA-B8, DR3 haplotype is highly conserved  and in linkage disequilibrium  with the tumour nectrosis factor (TNF*2) promoter allele which leads to a genetically high setting of TNF-α and C4AQ0, which leads to defect in opsonization and clearance of immune complexes. Studies in healthy individuals have revealed  an altered balance of cytokines  produced in carries of the haplotype such an impaired  production of IL-2, IL-5, IL-12 and INF-γ after a mitogen stimulus. The immune response is thus skewed towards Th2 cytokine production and the humoral response, although IL-5 production is also deperessed. Furthermore, both an increased production of autoantibodies and an increased blood lymphocyte spontaneous apoptosis are observed resulting in low levels of circulating lymphocytes.

Human Leukocyte Antigen (HLA) part 84

HLA and end-stage renal disease

Kidney failure is traditionally regarded as the most serious outcome of chronic kidney disease, and symptoms are usually caused by complications of reduced  kidney function. When symptoms are severe, they can be treated only by dialysis  and transplantation; kidney failure treated in this way is known as end-stage renal disease. The role of the HLA system in the pathophysiology of end-stage renal disease is intriguing, but not completely resolved. Numerous association  and non association of HLA with end-stage renal disease have been reported in the medical literature.

Human Leukocyte Antigen (HLA) part 83

During the era of donor-specific transfusion, patients were given blood from their prospective transplant donor, thypically three reduce volume transfusions during a period of 1-2 months. Under this protocols, many patients were transfused with blood from HLA-typed donors who had a variably degree of HLA match such as HLA-DR-matched transfusion. As expected, when more HLA antigens were matched, there was an independent association with a significantly decreased risk of sensitization.

Human Leukocyte Antigen (HLA) part 82

In the circulation, platelets have the greatest amount of circulating HLA class I molecules and  most of these HLA molecules are adsorbed on the platelets. The majority of HLA antigens  on the platelet surface are composed primarily of heavy chains; therefore, they have the ability to dissociate from the platelet  especially  with storage. When platelets are transfused into an allogenic recipient, the host is thus exposed to a huge dose of potentially altered donor HLA class I moleculles. The donor HLA molecules (whether still associated with the platelet or not) eventually circulate through the spleen and are either  phagocytosed (eg the platelet-associated class I) or taken up by pinocytosis (soluble class I) by cells (eg macrophages) of the reticuloendothelial system. These initial uptake mechanisms allow for recipient splenic macrophages .

Human Leukocyte Antigen (HLA) part 81

HLA and  Transfusion

The HLA class I antigens are carried in high concentration by leucocytes and platelets, but only in trace amounts on erytrocytes. Each transfusion of either platelets or leucocytes therefore carries a risk of immunizing the patient. Patients, with an intact immune system, who require multiple transfusions of whole blood, platelets or leucocyte concentrates, will therefore usually develop antibodies to HLA antigens. Anti-HLA antibodies may lead to two problems. Firstly, these patients become refractory to platelet transfusions, which they destroys rapidly, and secondly, non-haemolytic transfusion reactions may occur in response to HLA antigens.

Human Leukocyte Antigen (HLA) part 80

HLA-G,-E and -F are important regulators of the immune system, and their role in tumour immunology is attracting a steadily growing interest. The upregulation of HLA-G, -E and -F following interferon-γ stimulation suggests that non-classical HLA class I molecules may be involved  in negative feedback responses to potentially harmful pro-inflammatory responses. Inflammation is also one of the hallmarks  of cancer. While inflammatory responses  are required to eliminate cancer cells, they also trigger strong immuno-regulatory mechanisms that limit the recognition of malignant cells  by the immune system, hence favouring tumour suppression.  Thus, tumour results in the recruitment strongly immunosuppresive cells such as Tregs, myeloid-derived supressor cells and tumour infiltrating macrophages. Non-classical HLA class I molecules constitute another means whereby malignant cells escapes  immune-surveilance. Indeed, these molecules inhibit the activity of the immune system by binding to inhibitory receptors  expressed by effector cells, hence suppressing  their functions or inducing their apoptotic demise. Thus, the molecules  might become an important target for anticancer immunotherapy. Interfering with  the functions of non-classical HLA class I molecules might robustly  boost the antineoplastic  potential of cytotoxic effectors while antagonizing the activity of intrinsically immunosuppressive cells. The specific mechanisms whereby  these molecules  control excessive inflammation are currently under investigation for theurapeutic purposes, not only in the context of anticancer immunotherapy.

Human Leukocyte Antigen (HLA) part 79

The deviation include the complete absence or downregulation of HLA class I allo-specificities in frequent association to an impairment of a single  or various members of the antigen-processing and antigen-presenting machinery. In most cases, it seems that the HLA class I abnormalities result from a deregulation rather than a structural  defect suggesting an intervention at the epigenetic, transcriptional and or post transcriptional level. This observation increases even more the importance of studying  the crosstalk between the tumour cells and the microenvirontment.

Human Leukocyte Antigen (HLA) part 78

Downregulation or complete loss of HLA class I gene expression has been reported in variety of human solid and haematopoetic maligancies such as melanoma, colorectal, breast, lung and cervical carcinoma, and these changes were ranged from 3,4% to 60% depending on the tumour subtype analysed. In addition, loss of heterozygosity at the HLA loci is a frequent event in some tumour entities-like colorectal carcinoma and melanoma, but not in others, like renal cell carcinoma and could therefore contribute to the downregulate of HLA class I antigens in selected tumours types. The molecular mechanisms leading to defects in the HLA class I antigen presentation pathway have been well characterized upon viral infections. The human cytomegalovirus represents one suitable model for viral interference with the HLA class I antigen presentation pathway. For example,  the human cytomegalovirus encodes at least four proteins that impair the antigen-processing pathway at different steps from proteosomal degradation to peptide transport, formation of the trimeric HLA class I HC/β2 m/peptide complex to its transport to the cell surface. Furthermore, many other viruses also interfere with the HLA class I APM.

Human Leukocyte Antigen (HLA) part 77

HLA-A*02 allele is associated with poor prognosis in different cancers such as ovarian, prostate, melanoma and lung cancer. In the same time, in advance ovarian cancer, HLA-A2 is a negative clinical prognostic factor and it is phenotype overrepresented in both ovarian and prostate  cancer in Swedish patients compared to the normal population. At the genetic level, it is possible to consider  a linkage of HLA-A2 allele to putative onco- or tumour suppressor genes and could  explained the increased potential for oncogenic  transformation of cells and thus an increase mortality in these patients. At epigenetic level, it is speculated that a specific HLA-A2 micro RNA downregulate the HLA antigen expression in the HLA-A2 patients. During initial oncogenesis, the transformed cells may upregulate transcription of the major histocompatibility complex genes which served to absorb and engage the pool of miRNA. Potentially, this may prevent translation of HLA antigen message which impedes expression of HLA antigen and immune recognition. Moreover, normal regulatory functions of the miRNA are also compromised as the "decoy" transformed cells absorb and engage the available pool of miRNA.

Human Leukocyte Antigen (HLA) part 76

In humans, tumours alterations in the surface expression and/or function of HLA class I antigens are frequently found and equipt neoplastic cells with mechanisms to escape immune control. The aberrant expression of HLA class I molecules can be caused by structural alteration or dysregulations of genes encoding the classical HLA class I   antigens and/or components of the HLA class I APM. The dysregulation of APM components  could occur at the epigenetic, transcriptional or post-transcriptional level. Interestingly, none of the HLA class I and II alleles  have been demonstrated to be associated with an inctreased incidence per se of any cancer. However, individual alleles are known  to be overrepresented in certain cancers or  correlate with survival, prognosis, higher tumour staging, grading, disease progression and failure to CD8 T cells based immunotherapies.

Human Leukocyte Antigen (HLA) part 75

HLA AND CANCER

The theoritical model, which explains the manner through which there is unrestrained growth of cells that are different from those of the tissue from which they originate, is based on the modification of surface molecules that determine the recognition of celf-cells by the immunes ystem. Tumour cells do not respond to the regulatory stimuli that normally limit tissue proliferation. Carcinogens and oncogenic viruses activate gens that destabilize cell proliferation and repair. As a result, some cell-surface antigens are lost and others are expressed. At the end of this process, the tumour may no longer be recognized by the immune system. Structural and functional changes in HLA, loss of expression of tumour antigens, lack of co-stimulatory molecules and production of immunosuppresive cytokines are some of the possible mechanisms that cause tumour cells to escape immune surveillance.

Human Leukocyte Antigen (HLA) part 74

Both HLA-B27 and HLA-57 have been identified in terms both HIV and HCV infection. The mechanisms  for this joint efficacy could be manifold. First, it is possible that both HLA alleles could be in linkage disequilibrium with other genes in the major histocompatibility complex which are more directly responsible for their effects. Second,  it is possible that both HLA molecules select for epitopes that may have an influence on viral fitness. Third, it is possible that such associations are simply related to the prevalence of a particular gene in a population  because it is likely that in any given population there will be less exposure to and consequently less selection against, rare alleles, particularly in population where the prevalence of the condition has increased recently. It is worth noting that there are also striking differences between HIV and HCV in HLA types association with protection.