Biochemistry, HLA Antigens


Article Author:
Helen Nordquist


Article Editor:
Radia Jamil


Editors In Chief:
Hela Kchir
Joseph Lee
Savio John


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
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Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
8/25/2019 4:55:11 AM

Introduction

Human leukocyte antigens (HLA) are genes in major histocompatibility complexes (MHC) that help code for proteins that differentiate between self and non-self. They play a significant role in disease and immune defense. They are beneficial to the immune system, but can also have detrimental effects. Some of the immune system effects are the interaction with complement, the cytotoxic effect of T cells, and cellular humoral immunity. Additionally, they play a role in autoimmunity and continue to be the target of researchers for their further effects and interactions.[1]

Fundamentals

HLA are of three main types. Class I HLA antigens include HLA-A, B, and C molecules; class II, which includes HLA-DR, -DQ, and -DP loci, are on antigen-presenting cells; and class III contains genes for proteins that have immune functionality.[1]

Issues of Concern

HLA antigen sensitization can become a problem for patients undergoing procedures such as stem cell transplant. HLA antigens have a significant role in transplant-mediated rejection, which falls under the following two categories:

T-cell-mediated rejection

In T-cell-mediated rejection, the T-cell becomes activated because of the interaction between the T-cell receptor and the HLA-peptide combination from the donor.

Antibody-mediated rejection

In antibody-mediated rejection, the T-helper cells are co-stimulated, and there is a concurrent inflammatory response, leading to the recognition of foreign HLA molecules. 

Due to the possibility of these two types of rejection, laboratories measure the HLA antibodies in circulation to determine the risk of rejection.[1]

HLA types also had correlations with an increased risk of particular diseases. For example, early-onset myasthenia gravis correlates with HLA-B8 as the unique genetic factor that leads to the onset of the disease[2] Multiple sclerosis, although of unknown etiology, has been shown to have a high rate of correlation with the HLA-DR2 antigen.[3] Additionally, rheumatoid arthritis (RA) has been shown to precipitate from complex biological interactions in the body. Some of these interactions include HLA-DR4, a glycopeptide from type II collagen, and a T-cell receptor, shown to be correlated with the development of RA.[4]

Cellular

The HLA class I is on all nucleated cell surfaces and presents intracellular peptides to cytotoxic T-cells in the immune system.[4]

HLA plays a role in cellular immunity, particularly noted in transplant reactions. Particular antibodies, such as anti-HLA-B and anti-HLA-DQ, can bind complement.[5]

Molecular

HLA antigens can be variable, and researchers have been investigating their presence and function to determine their use in disease diagnosis and treatment. HLA polymorphisms can change depending on the epidemiological composition of a particular population, so this presents an important area of research to further delve into as technology progresses. Studies can be done on specific demographics of humans to research more about the presence of particular diseases that have a predilection in certain groups. For example, in 2018, there was a trial conducted in Thailand to evaluate the efficacy of a Dengue vaccine. The HLA antigens were mapped in the population, and researchers identified 201 different HLA antigens through next-generation sequencing techniques. Through this investigation, researchers were able to identify HLA alleles that had higher frequencies in the population and were able to incorporate that information and to begin to apply it to disease association in the population.[6]

Function

HLA antigens, particularly the A, B, and C loci, are highly variable, especially in the extracellular domains, as evidenced by the over 300 class I alleles that researchers have identified.[5] The parts of the HLA antigens that are the most variable reside near the peptide-binding groove. The variability alters the interactions with T-cell receptors and the peptide-binding specificity; this changes the function of the HLA antigens, which can alter the immune response and disease resistance.[4]

In addition to their variability and function as peptide receptors, they act at different sites with beta-2-microglobulin, an alpha-beta T-cell receptor, and inhibitory molecules.[7] The various alleles within each class of HLA antigens allow for these additional functions.

Testing

Types of tests include cellular assays, immunologic, and molecular.

Conventionally, HLA classes are detectable by the polymerase chain reaction (PCR). PCR uses variable exon sequences that encode the first amino-terminal from the HLA domains. From there, the HLA sequences from the database are used in hybridization with the amplified PCR products.[8]

There have also been recent developments in less expensive assays to detect specific HLA antigens, such as high-resolution melting assays.[9]

The standard technique for identifying HLA class I and class II antigens has been the complement-mediated microlymphocytotoxicity technique. In this technique, HLA sera are obtained from alloimmunized women, and those specificities get determined by matching against a panel with already known HLA types.[8]

Testing for HLA antigens often is by bead-based multiplexed immunoassay system technology. In this test, HLA protein beads coat the surface of microspheres. A fluorescence quantification system measures the level of HLA antibody binding to each of the beads. 

Testing in patients with HLA antibodies in their circulation requires a cross-match before transplantation. This traditional cross-match entails patient serum mixed with lymphocytes that have derived from the donor. "Virtual" cross matches may also be done to estimate the transplant risk by measuring the levels of circulating HLA antibody using single antigen beads and bead-based multiplexed immunoassay system technology.[3]

Pathophysiology

Often, the specific pathophysiology for how HLA antigens are associated with a disease is not well known. However, HLA antigens play a role in autoimmunity. For example, in type I diabetes mellitus, the DR3-DQ2 haplotype is seen at an increased percent compared to the general population. The same haplotype is also associated with juvenile autoimmune thyroiditis. Other haplotypes can be protective for diseases, such as DRB1*14:01, which has protective effects against type I diabetes.[10]

Clinical Significance

Graft-versus-host disease

A major clinical significance of HLA antigens is their role in transplant rejection.

The opposite can occur when immune cells get transplanted with the graft into the recipient. Hematopoietic progenitor cell transplantation (e.g., bone marrow, stem cells) must mainly deal with this phenomenon. Graft-versus-host disease (GVHD) is influenceable by the presence of donor antibodies against HLA class II antigens. In a study done at Henri-Mondor University Hospital in France, they demonstrated that when donors have the antibodies against the specific recipient HLA antigens, there is a correlation with the incidence of GVHD.[3]

A study in the UK of stem cell transplants between 1996 and 2003 showed that patients with a class I HLA mismatch were more likely to developed chronic GVHD. Additionally, the pairs that had the mismatches also had a higher mortality rate after one year. Multiple HLA mismatches show higher rates of GVHD.[11]

HLA antigens are matchable when administering blood products. Research has demonstrated that blood banks that use the HLA genotypes of the blood donors have better transfusion outcomes. There has been a discussion of the possibility of creating a database with genotyped donors to make it slightly easier to find blood for patients with rare HLA antibodies so that their transfusions can have less risk of adverse outcomes because of having matched donors.[12]

As discussed above, studies have identified particular HLA antigens have as correlating with disease processes. These allow for the development of specific treatments for diseases.

Multiple Sclerosis

HLA-DR2 is associated with multiple sclerosis. Since there is such a strong association between the disease and the antigen, there have been studies looking at immunotherapy to target the DR2 antigen in the treatment of the disease. In one particular study, the molecule PV-267 was examined for its promise as a therapy. PV-267 functions as a cytokine inhibitor and inhibits the proliferation of myelin-specific DR2 antigens. By using PV-267 derived from multiple sclerosis patients, researchers found the potential for further therapeutic options.[13]

Rheumatoid Arthritis

Rheumatoid arthritis shows strong associations with DR4. These have been thought to indicate disease susceptibility. When DR4 binds with a class II-associated peptide, it may indicate an increased risk for rheumatoid arthritis. The DR4 binding changes the presentation of the citrullinated peptides, which contributes to the development of the disease.[14]

Graves Disease

Graves disease is associated with HLA-DR3. In addition to environmental factors, HLA haplotype plays a significant role in disease development. Important clinically, HLA typing may help to predict the outcome of Graves disease before and post-antithyroid medical therapy.[15] The typing can be used to associate increased and decreased allele values during therapy.[16]

Behçet Disease

Behçet Disease is associated with HLA-B51, which influences the clinical features of the disease. Patients with the HLA-B51 haplotype have been shown to develop symptoms of the disease earlier in life (less than 40 years of age). Additionally, neurological and gastrointestinal symptoms of the disease were more prevalent in patients without the HLA-B51 haplotype, rather than those who had it.[17]


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Biochemistry, HLA Antigens - Questions

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A 32-year-old male presents to his family care provider with chronic low back pain that is worse in the mornings and has slowly progressed over 6 months. He states that he started walking in the evenings to try to lose weight and notice that his right heel has become increasingly painful, with minor swelling around the ankle when standing. He attributes the heel pain to walking in the wrong type of shoes. On physical exam, you notice small sharply demarcated plaques on the patient's elbows. His blood pressure is 135/91 mm Hg, his pulse is 84 beats per minute, and respirations are 15 breaths per minute. Which of the following human leukocyte antigen would you expect to be positive in this patient?



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A 65-year-old male with a past medical history of hypertension and acute myeloid leukemia presents to the clinic with reports of weakness and fatigue. His physical exam shows pallor. His labs show hemoglobin of 6.6 g/dL. He requires an RBC transfusion that needs care to avoid transfusion-associated graft vs. host disease, which is associated with HLA-class II antigens. Which of HLA antigen types would only be present on dendritic cells?



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A 17-year-old female presents to her healthcare provider with new-onset weakness, muscle spasms, and trouble seeing. Her mother has rheumatoid arthritis, and her older sister has type I diabetes. What type of HLA antigens is the patient most likely to have?



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A 65-year-old man with type O-positive blood comes to the emergency department with reports of bright red blood in his stool over the past week and a 15-pound weight loss over the last three months. He also says that he is feeling really weak, especially over the previous two mornings when he woke up. On physical exam, skin pallor is observed. His laboratory findings demonstrate hemoglobin of 6.7 g/dL. What is the crucial step to preventing the attack of HLA-class II expressing tissues if blood products are administered to correct his low hemoglobin level?



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A 35-year-old woman presents with a 4-month history of bloody stool, diarrhea, and abdominal pain. She says that she "has always had a sensitive stomach," but diarrhea and bloody stool over the last few months have been new. She reports that she has tried eliminating gluten and dairy from her diet, but nothing has helped. She has lost 5 pounds over this time period and is frustrated that she has had to deal with this. Her physical exam shows moderate abdominal tenderness in the left lower quadrant and a positive fecal occult blood test. She is found to be HLA-B5 positive. What is the most likely cause of her symptoms?



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Biochemistry, HLA Antigens - References

References

Carey BS,Poulton KV,Poles A, Factors affecting HLA expression: A review. International journal of immunogenetics. 2019 Jun 10;     [PubMed]
Delbos F,Barhoumi W,Cabanne L,Beckerich F,Robin C,Redjoul R,Astati S,Toma A,Pautas C,Ansart-Pirenne H,Cordonnier C,Bierling P,Maury S, Donor Immunization Against Human Leukocyte Class II Antigens is a Risk Factor for Graft-versus-Host Disease. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2016 Feb;     [PubMed]
Parham P, Function and polymorphism of human leukocyte antigen-A,B,C molecules. The American journal of medicine. 1988 Dec 23;     [PubMed]
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Geretz A,Ehrenberg PK,Bouckenooghe A,Fernández Viña MA,Michael NL,Chansinghakule D,Limkittikul K,Thomas R, Full-length next-generation sequencing of HLA class I and II genes in a cohort from Thailand. Human immunology. 2018 Nov;     [PubMed]
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Fawwad A,Govender D,Ahmedani MY,Basit A,Lane JA,Mack SJ,Atkinson MA,Henry Wasserfall C,Ogle GD,Noble JA, Clinical features, biochemistry and HLA-DRB1 status in youth-onset type 1 diabetes in Pakistan. Diabetes research and clinical practice. 2019 Mar;     [PubMed]
Shaw BE, The clinical implications of HLA mismatches in unrelated donor haematopoietic cell transplantation. International journal of immunogenetics. 2008 Aug;     [PubMed]
Dutra VF,Bub CB,Costa TH,Santos LD,Bastos EP,Aravechia MG,Kutner JM, Allele and haplotype frequencies of human platelet and leukocyte antigens in platelet donors. Einstein (Sao Paulo, Brazil). 2019 Feb 7;     [PubMed]
Andrews LP,Clark RK,Damjanov I, Mixed glycosidase pretreatment reduces nonspecific binding of antibodies to frozen tissue sections. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 1985 Jul;     [PubMed]
Miyadera H,Tokunaga K, Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism. Journal of human genetics. 2015 Nov;     [PubMed]
Matsuo T,Ushiroda Y, IDENTICAL TWIN SISTERS WITH CLOSE ONSET OF GRAVES' DISEASE AND WITH MULTIPLE HLA SUSCEPTIBILITY ALLELES FOR GRAVES' DISEASE. Acta endocrinologica (Bucharest, Romania : 2005). 2016 Jan-Mar;     [PubMed]
Vita R,Lapa D,Trimarchi F,Vita G,Fallahi P,Antonelli A,Benvenga S, Certain HLA alleles are associated with stress-triggered Graves' disease and influence its course. Endocrine. 2017 Jan;     [PubMed]
Ryu HJ,Seo MR,Choi HJ,Baek HJ, Clinical phenotypes of Korean patients with Behcet disease according to gender, age at onset, and HLA-B51. The Korean journal of internal medicine. 2018 Sep;     [PubMed]

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