hla transplantation and complement

HLA Transplantation and Complement

Dr. Muhammad Yahya Noori

Based upon Warren Levinson 1

Human Leukocyte Antigen

• The success of tissue and organ transplants depends on the donor's and recipient's human leukocyte antigens (HLA) encoded by the HLA genes.

• These proteins are alloantigens

(They differ among members of the same species)

• If the HLA proteins on the donor's cells differ from those on the recipient's cells, an immune response occurs in the recipient.


Major Histocompatibility Complex

• The genes for the HLA proteins are clustered in the major histocompatibility complex (MHC), located on the short arm of chromosome 6– Three of these genes (HLA-A, HLA-B,

and HLA-C) code for the class I MHC proteins.

– Several HLA-D loci determine the class II MHC proteins, i.e., DP, DQ, and DR

– Class I MHC proteins are found on the surface of all nucleated cells, including those that have class II MHC proteins.


MHC Proteins

Class I MHC Proteins

• These are glycoproteins found on the surface of virtually all nucleated cells.

• The complete class I protein is composed of a 45,000-molecular weight heavy chain non-covalently bound to a Beta 2-microglobulin.

• The polymorphism of these molecules is important in the recognition of self and non-self.

CLASS II MHC PROTEINS

• These are glycoproteins found on the surface of certain cells, including macrophages, B cells, dendritic cells of the spleen, and Langerhans' cells of the skin.

• They are highly polymorphic glycoproteins composed of two polypeptides (MW 33,000 and 28,000) that are non-covalently bound.

• Like class I proteins, they have hypervariable regions that provide much of the polymorphism. Based upon Warren Levinson 4

A comparison between MHC I and II


Mode of HLA Expression

• Each person has two haplotypes– one on the paternal chromosome– Other on the maternal chromosome

• These genes are polymorphic– For example, there are at least 47 HLA-A genes, 88 HLA-B genes, 29 HLA-C genes, and

more than 300 HLA-D genes, but any individual inherits only a single allele at each locus from each parent and thus can make no more than 2 class I and II proteinsat each gene locus.

– Expression of these genes is codominant– Each person can make as many as 12 different HLA proteins– 3 at class I loci and 3 at class II loci, from both chromosomes. – There are an unknown number of minor antigens encoded by genes at sites other than

the HLA locus that can lead to slow graft rejection.


Biological Importance of MHC

• The ability of T cells to recognize antigen is dependent on association of the antigen with either class I or class II proteins.

• For example, cytotoxic T cells respond to antigen in association with class I MHC proteins.

• Helper cell activity depends on both the recognition of the antigen on antigen-presenting cells and the presence on these cells of "self" class II MHC proteins.

• This requirement to recognize antigen in association with a "self" MHC protein is called MHC restriction.


TransplantTerminology

Autograft: Transfer of an individual's own tissue to another site in the body is always permanently acceptedSyngeneic graft:A transfer of tissue between genetically identical individualsXenograftA transfer of tissue between different species, is always rejected by an immunocompetent recipient.AllograftA graft between genetically different members of the same species


Transplant Rejection

• Unless immunosuppressive measures are taken, allografts are rejected by a process called the allograft reaction.

• In an acute allograft reaction, vascularization of the graft is normal initially, but in 11 to 14 days, marked reduction in circulation and mononuclear cell infiltration occurs, with eventual necrosis.

• This is called a primary (first-set) reaction. • A T-cell–mediated reaction is the main cause of rejection

of many types of grafts, e.g., skin• Antibodies contribute to the rejection of certain

transplants, especially bone marrow


Graft Versus Host Reaction

• Well-matched transplants of bone marrow may establish themselves initially in 85% of recipients, but subsequently a graft versus-host (GVH) reaction develops in about two-thirds of them.

• This reaction occurs because grafted immunocompetent T cells proliferate in the irradiated, immunocompromised host and reject cells with "foreign" proteins, resulting in severe organ dysfunction.

• The donor's cytotoxic T cells play a major role in destroying the recipient's cells. Among the main symptoms are maculopapular rash, jaundice, hepatosplenomegaly, and diarrhea .

• Many GVH reactions end in overwhelming infections and death.• There are three requirements for a GVH reaction to occur:

– The graft must contain immunocompetent T cells– The host must be immunocompromised– The recipient must express antigens (e.g., MHC proteins) foreign to the donor


Complement

• The complement system consists of approximately 20 proteins that are present in normal human (and other animal) serum.

• The term "complement" refers to the ability of these proteins to complement, i.e., augment, the effects of other components ofthe immune system, e.g., antibody.

• Complement is an important component of our innate host defenses.

• There are three main effects of complement: – Lysis of cells such a s bacteria , allografts, and tumor cells– Generation of mediators that participate in inflammation and attract

neutrophils– Opsonization, i.e., enha ncement of pha gocytosis.

Complement proteins a re synthesized ma inly by the liver.


Complement Activation


Regulation of Complement

OpsonizationMicrobes are phagocytized much better in the presence of C3b.

Chemotaxis5a and the C5,6,7 complex attract neutrophils.

AnaphylatoxinC3a , C4a , and C5a cause degranulation of mast cells. Ana phyla toxins can also bind directly to smooth muscle cells of the bronchioles

CytolysisInsertion of the C5b,6,7,8,9 complex into the cell membrane leads to killing or lysis of many types of cells

Enhancement of Antibody ProductioNThe binding of C3b to its receptors on the surface of activated B cells greatly enhances antibody production


hla transplantation and complement

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