Introductory Chapter: Human Leukocyte Antigens – Updates and Advances

1. Introduction

Organ transplantation has always been and continues to be a matter of curiosity. Transplantation of a healthy organ from a living donor or cadaver instead of an organ that cannot function in the body is called organ transplantation. The knowledge on immunology and immunosuppression has brought organ transplants to the agenda in the contemporary sense [1]. The most important aim of organ transplantation is to save the life of a person who is about to die due to organ failure, to increase the quality of life and to prolong its duration. Organ transplantation is accepted as a valid and advanced treatment method applied in many chronic organ diseases today. One of the basic steps of organ transplantation is constituted by tissue compatibility antigens.

HLA, which is called “Tissue Compatibility Antigens” or “Transplantation Antigens” necessary for the immune system to recognize foreign antigens, came from the abbreviation “Human Leukocyte Antigens” because they were first shown in leukocytes. The gene region encoding these human leukocyte antigens, which is necessary for the immune system to recognize self and non-self, is located on the sixth chromosome in humans and is called the Major Histocompatibility Complex Gene Region (MHC). Tissue compatibility antigens are also called MHC antigens. The discovery of the major tissue compatibility complex dates back to the 1940s [2]. The MHC consists of about 100 separate genes, and in this region, which is about 4000 kilobases in size, and there are some genes that have not been identified that are related to the immune response. MHC is divided into subregions as Class I, II, and III according to the characteristics of the encoded proteins [3, 4, 5].

HLA antigens encoded by polymorphic MHC genes are one of the most important elements of the immune system. Thanks to these, a bridge can be established between the natural immune system and the acquired immune system. In addition, the effective functioning of other elements of the acquired immune system, especially T cells, is provided by MHC molecules. From an evolutionary point of view, the sustained life on earth is, in a way, guaranteed thanks to the increased diversity of MHC alleles. However, such diversity in HLA alleles continues to be the most important factor in creating susceptibility or resistance to autoimmune and infectious diseases and preventing the success of organ transplantations.

HLA is an alloantigen that differs individually within the same species. In the following years of the discoveries, it was understood that they were found in all somatic cells, and it was shown that they have a very important role in tissue transplantation and that they determine the success of transplantation [6]. It was determined in the 1970s that people with a certain tissue type are more prone to certain diseases. In recent years, with the usage of recombinant DNA methods in which MHC molecules are crystallized, the base sequence of MHC complex genes and the amino acid sequences of MHC antigens that these genes provide synthesis have been revealed [7].

Clinical HLA applications are used for, transplantation, disease studies, anthropological studies, and paternity testing [8]. There are many studies proving the importance of HLA antigen compatibility, especially in bone marrow transplants [9, 10]. After the observation that MHC differences trigger tissue rejection, a lot of effort was spent to define these antigen differences. Unrelated donor sources are an important alternative for allogenic bone marrow transplantation, which is a curative treatment alternative in hematopoietic system malignancies and diseases where there is no suitable relative donor. An advanced HLA tissue bank system is needed to find an HLA-matched unrelated donor. The higher the capacity of HLA tissue banks, the higher the chance of finding a suitable donor. Again, in solid organ transplantation, tissue rejection has been tried to be minimalized by matching the HLA antigens of the donor and the recipient. Generally, the more alleles are compatible, the better the graft survival [11]. Studies have shown that MHC is associated with many diseases, especially infectious and autoimmune-based diseases. Such studies are carried out to determine disease risks and protective factors and to plan treatments [12].

Advances in technology and molecular diagnostic methods have facilitated the identification of HLA alleles that are important in organ and tissue transplants. Advantages of molecular methods: they are unique and flexible, new reagents can be developed as new alleles are identified, there are options that can perform studies with the desired sensitivity, they do not require live cells in studies, they are not affected by disease or treatment status of the individual, and they are more suitable for automation compared to serological and cellular methods, simultaneously. It can be summarized as being able to study a large number of samples, showing all the diversity in HLA genes and recognizing alleles that cannot be identified serologically.

Importance of MHC molecules in tissue transplantation: Immune responses after transplantation occur by well-defined mechanisms. Assuming that the recipient has not been sensitized before, the first responses include natural and non-antigen specific ones. Although natural immunity is not specific, it occurs rapidly and includes cellular elements such as neutrophils, macrophages, dentritic cells, NK and molecular elements such as toll like receptor(TLR), complement system, chemokine, cytokine [13]. The inflammation that occurs after the first encounter allows the antigen-presenting cells to mature and migrate to the lymphoid organs. In secondary lymphoid organs, dentritic cells initiate the acquired phase of the immune response by activating naive T cells. After the antigen-presenting cells activate the T cells, the acquired immune response phase begins. There are two ways in which alloantigens are recognized by the recipient’s T cell. Indirect recognition, the recipient’s T lymphocytes are triggered by alloantigens expressed on the donor antigen-presenting cell. These antigen-presenting cells are called passenger leukocytes, and they migrate from the transplanted organ to the recipient’s secondary lymph nodes. These alloantigens are composed of endogenous peptides that have formed a complex with the donor MHC [14]. If the peptide presented with MHC is not an intrinsic peptide, it is perceived as a ‘foreign’ by the alloreactive T cell and leads to T cell activation. In indirect recognition, alloantigens on the donor cells are captured, processed by the recipient’s cells and presented to the recipient T lymphocytes in the slit of the native MHC molecule. The recognition of alloantigen by T cells ends with T cell activation, proliferation, elimination of the antigen. MHC molecules also appear to be responsible for post-transplant rejections.

Importance of MHC molecules in cancer: MHC molecules have an important role in tumor cells defeating the immune system. Tumor cells begin to produce new proteins called tumor antigens. These proteins, which are considered foreign by the immune system, are captured by APC, processed and presented to CD8+ T cells by MHC I molecules. As a result, a cytotoxic reaction against tumor cells begins. However, although tumor antigens are newly produced foreign antigens, since they originate from self-antigens, they are similar in structure to them and cannot stimulate the immune response very well. This causes the tumor cell to escape from the immune system. On the other hand, it is seen that MHC expressions are suppressed in tumor cells over time. In this way, tumor antigens are hidden from the immune system. This again causes tumor cells to escape from the immune system [15].

We wanted to highlight the important points about HLA with the knowledge and light of our academics who wrote the chapters of this book. Our academics are written by our departments by examining important topics to better illuminate, clarify, and guide future generations. We present our book chapter to all readers interested in transplantation immunology.

2. Conclusion

In conclusion, HLA antigens encoded by polymorphic MHC genes are one of the most important elements of the immune system. In addition to the high polymorphism feature, the codominant inheritance of MHC genes and the continuation of mutations in these genes cause a high level of immunological diversity among individuals in the population. It emphasizes its evolutionary importance as well as its contribution to the sustained continuation of life on earth. However, such diversity in HLA alleles continues to be the most important factor in creating susceptibility or resistance to autoimmune and infectious diseases and preventing the success of tissue transplantations. For this reason, better knowledge of HLA gene regions, structure, and function of HLA molecules will shed light on disease susceptibility, resistance formation, transplantation, and studies in the medical world.

We think you can find updates on HLA and transplantation in this book. We think we provide information that supports academics. The advancement of technology and science will continue to expand our knowledge.

Conflict of interest

The author declares no conflict of interest.