1. Human leukocyte antigen (HLA) system

The human leukocyte antigen (HLA) system, also known as the major histocompatibility complex (MHC), is a complex of genes located on chromosome 6 in humans that encode cell-surface proteins responsible for regulating the immune system. The HLA system is a crucial part of the body's defense against disease, as it helps to distinguish between self and non-self cells. Mutations in HLA genes have been linked to various autoimmune diseases, including type 1 diabetes and celiac disease. The HLA gene complex is also responsible for organ transplant rejection, making HLA typing an essential tool in transplantation.

Generally, the HLA system is divided into two classes: HLA class I (HLA -A, -B-, -C) and class II (HLA-DR, -DP, -DQ). HLA glycoproteins contribute decisively to the defense against foreign antigens (infections) and control the immunological identity of a given individual. Indeed, it is the genetic system which was already at the beginning of the 20th century postulated by Paul Ehrlich to be responsible for the differentiation between "self" and "non-self" or, in other words, between tolerance (towards own tissue/organs) and active immune defense (against foreign invaders). Today, we know that HLA-antigens direct the sophisticated interplay between B- and T-lymphocytes during the specific defense of the so-called acquired immune system.

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Human leukocyte antigen (HLA) system
HLA Gene Complex
HLA Class I Molecules
HLA Class II Molecules
HLA Class III Molecules
HLA and Autoimmune Diseases
HLA Typing
Conclusion

2. HLA Gene Complex

2.1. Location and structure

The HLA gene complex is located on the short arm of chromosome 6, at position 21.3, and spans a 3 Mbp stretch. The complex includes genes that encode for various cell-surface proteins, including HLA Class I and II molecules and components of the complement system. The HLA system is highly polymorphic, with many alleles for each HLA gene, allowing for a diverse array of antigen presentations.

2.2. Polymorphism

HLA genes are highly polymorphic, meaning they have many alleles that allow for fine-tuning of the adaptive immune system. This diversity is essential to disease defense, as the chance of two unrelated individuals with identical HLA molecules on all loci is extremely low. Polymorphism is also a key factor in organ transplantation, as matching donors and recipients for HLA types is crucial to prevent transplant rejection.

2.3. Relationship to MHC

The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals. MHC genes are involved in immune response, and the HLA system encodes the MHC molecules in humans. The HLA system includes genes that encode for both HLA Class I and II molecules, presenting peptides from inside and outside the cell.

3. HLA Class I Molecules

3.1. Function

HLA class I molecules are a group of three HLA genes: HLA-A, HLA-B, and HLA-C. These molecules present peptides inside the cell, allowing the immune system to identify and destroy infected or abnormal cells. HLA class I molecules are critical for cell-mediated immunity, which involves T-cells recognizing and destroying abnormal or infected cells.

3.2. Peptide presentation

HLA class I molecules present peptides that are produced from proteins that are broken down in proteasomes. The resulting peptides are typically small polymers, around 8-10 amino acids in length, although recent research has shown that longer peptides (11-14 amino acids) can also be presented on MHC I molecules. Foreign antigens presented by MHC Class I molecules attract T-lymphocytes called killer T-cells, which destroy cells.

3.3. Role in the immune system

HLA class I molecules play a critical role in the immune system by identifying and destroying infected or abnormal cells. When a cell is infected with a virus, for example, HLA Class I molecules bring fragments of the virus to the cell's surface, allowing killer T-cells to recognize and destroy the infected cell. This process is vital to the body's defense against infectious diseases.

3.4. Killer T-cells

Killer T-cells, also called CD8-positive or cytotoxic T-cells, are T-lymphocytes that recognize and destroy cells that display foreign antigens. These cells are critical for cell-mediated immunity and play a vital role in the body's defense against infectious diseases. HLA class I molecules are crucial in activating killer T-cells and directing them to destroy infected or abnormal cells.

4. HLA Class II Molecules

4.1. Function

HLA Class II molecules are a group of HLA genes that present peptides from outside the cell, allowing the immune system to recognize and destroy extracellular pathogens. HLA Class II molecules are responsible for stimulating the multiplication of T-helper cells, which in turn stimulate the production of antibodies by B-cells.

4.2. Peptide presentation

HLA Class II molecules present antigens from outside of the cell to T-lymphocytes. These antigens stimulate the multiplication of T-helper cells, which then stimulate antibody-producing B-cells to produce antibodies to that specific antigen. Regulatory T-cells suppress self-antigens.

4.3. Role in the immune system

HLA Class II molecules play a critical role in the immune system by identifying and destroying extracellular pathogens. By presenting antigens to T-helper cells, HLA Class II molecules stimulate the production of antibodies by B-cells, which can recognize and destroy extracellular pathogens. This process is vital to the body's defense against infectious diseases.

4.4. T-helper cells

T-helper cells, called CD4-positive T-cells, are T-lymphocytes that recognize antigens presented by HLA Class II molecules. These cells are critical for stimulating the production of antibodies by B-cells, which can identify and destroy extracellular pathogens. HLA Class II molecules are crucial in activating T-helper cells and directing them to produce antibodies.

5. HLA Class III Molecules

5.1. Function

HLA Class III molecules are a group of HLA genes that encode components of the complement system, a part of the immune system that helps destroy foreign invaders. The complement system consists of a group of proteins that work together to kill bacteria and viruses by forming a membrane attack complex that punctures the cell membrane of the invading microbe.

5.2. Role in disease defense

HLA Class III molecules are essential in disease defense, as they play a critical role in activating the complement system. The complement system is integral to the body's protection against infectious diseases and destroys bacteria and viruses. HLA Class III molecules are responsible for encoding the proteins that comprise the complement system and, thus, are essential for proper functioning.

5.3. Relationship to organ transplant rejection

HLA Class III molecules are also involved in organ transplant rejection. In addition to HLA Class I and Class II molecules, HLA Class III molecules play a role in the immune response to transplanted tissue. The proteins encoded by the HLA Class III genes are involved in the inflammatory response that can lead to transplant rejection.

5.4. Other functions

HLA Class III molecules have also been linked to other biological processes, such as apoptosis (programmed cell death) and the regulation of the immune response. Some research has suggested that specific HLA Class III alleles may be associated with an increased risk of developing certain diseases, such as Alzheimer's and autoimmune disorders.

6. HLA and Autoimmune Diseases

6.1. Relationship between HLA and autoimmune diseases

HLA molecules are inherited, and certain HLA types are connected with autoimmune disorders and other diseases. People with specific HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, ankylosing spondylitis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, myasthenia gravis, inclusion body myositis, Sjögren syndrome, and narcolepsy.

6.2. Relative risk of developing autoimmune diseases

Different HLA alleles are associated with other autoimmune disorders, and the relative risk of developing these diseases varies depending on the HLA type. For example, the HLA-B27 allele increases the risk of developing ankylosing spondylitis, reactive arthritis, and acute anterior uveitis. The HLA-DR2 allele is associated with an increased risk of developing systemic lupus erythematosus. The HLA-DR3 allele is associated with an increased risk of developing autoimmune hepatitis, primary Sjögren syndrome and type I diabetes.

6.3. HLA typing in diagnosis and treatment

HLA typing is used as a tool in the diagnosis and treatment of autoimmune diseases. For example, HLA typing has improved the diagnosis of celiac disease and type I diabetes. In celiac disease, HLA typing is the only effective means of discriminating between firs

t-degree relatives who are at risk from those who are not at risk before the appearance of sometimes-irreversible symptoms.

6.4. HLA and cancer

HLA-mediated diseases are also involved in the promotion of cancer. Gluten-sensitive enteropathy, for example, is associated with an increased prevalence of enteropathy-associated T-cell lymphoma, and DR3-DQ2 homozygotes are within the highest risk group, with nearly 80% of gluten-sensitive enteropathy-associated T-cell lymphoma cases. Abnormal cells might be targeted for apoptosis, which is thought to mediate many cancers before diagnosis.

7. HLA Typing

7.1. Importance of HLA typing

HLA typing is a laboratory test that determines a person's HLA antigens. HLA typing is essential for several reasons, such as matching donors and recipients for organ transplantation, predicting the risk of developing certain diseases, and determining the best treatment for some autoimmune diseases.

7.2. Techniques for HLA typing

There are several techniques for HLA typing, including serological methods, which use antibodies to detect HLA antigens on the surface of cells, and molecular methods, which use PCR (polymerase chain reaction) to amplify HLA genes for analysis. PCR-based methods are becoming more widely used for HLA typing due to their higher resolution and ability to detect rare alleles.

7.3. Limitations of HLA typing

Despite its importance, HLA typing has some limitations. The HLA system is highly polymorphic, meaning many alleles exist for each HLA gene, making it challenging to identify a perfect match for transplantation. In addition, HLA typing can be expensive and time-consuming, and the interpretation of results can be difficult, particularly for rare or novel HLA alleles.

7.4. New developments in HLA typing

New developments in HLA typing make it easier to perform and interpret HLA typing results. Next-generation sequencing (NGS) is a technique that can sequence large amounts of DNA in a single run, allowing for more complete and accurate HLA typing results. Other advances include improved software for HLA typing analysis, which can help to overcome some of the challenges associated with interpreting HLA typing results.

8. Conclusion

The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 that encode cell-surface proteins responsible for the regulation of the immune system. The HLA system plays a crucial role in disease defense, as it presents antigens to T-cells, which play a critical role in the immune response to foreign invaders.

HLA genes are highly polymorphic, meaning that each gene has many different alleles, which allows for a fine-tuning of the adaptive immune response. Mutations in HLA genes have been linked to autoimmune diseases, such as type I diabetes and celiac disease, and are also involved in transplant rejection.

In addition to their role in the immune response, HLA antigens have also been linked to other biological processes, such as mate selection and the perception of the odor of other people.

HLA typing is an important laboratory test that determines a person's HLA antigens, which is crucial for matching donors and recipients for organ transplantation, predicting the risk of developing certain diseases, and choosing the best course of treatment for some autoimmune diseases.

The HLA system is a critical component of the human immune system. Understanding its function and role in disease defense is essential for developing new treatments and therapies for various diseases.