MHC HLA

CLBT 1050: SEROLOGY & IMMUNOLOGY

NATURE OF ANTIGENS

MHC AND HLA

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CHARACTERISTICS

  • Group of 6 Genes
  • Function: Genes code for production of HLA antigen found on the surface of all nucleated cells.
  • Significance: MHC is important for:
    • Paternity testing.
    • Tissue typing for transplants (donor and recipient).
  • Terminology:
    • MHC was originally referred to as HLA (human leukocyte antigen).
    • Present on all nucleated cells.
  • Role:
    • Pivotal in development of humoral and cell-mediated immunity.
    • T cell activation occurs only when the antigen (Ag) is combined with MHC molecule on the surface of other cells.
  • Genetic Characteristics:
    • MHC genes are inherited as closely linked haplotypes (one from each parent).
    • Highest expression in lymphoid and myeloid cells.
  • MHC Class III:
    • Main role is antigen presentation, which is the process of transporting degraded peptides to the plasma membrane for T cell recognition.
  • Dendritic Cells:
    • Have the highest class # of MHC and are the most effective antigen presenting cells.

NATURE OF ANTIGENS - HLA (HUMAN LYMPHOCYTE ANTIGEN) ORIGIN

  • Origin: Originally found on surface of lymphocytes.
  • Location: Actually found on the surface of all nucleated cells, including tissue cells.

MHC vs HLA ANTIGENS

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
  • MHC Gene Location: On DNA chromosome #6.
HLA ANTIGEN
  • Location: On the surface of blood & tissue cells.
  • Application: Used in paternity testing and tissue typing for organ transplant.

CATEGORIES OF MHC

  • Categories of MHC Genes:
    • Class I (A, B, C)
    • Class II (DP, DQ, DR, DM)
    • Class III (inherited by both parents as haplotypes).

CLASS I MHC GENES

  • Location: Chromosome #6 at loci A, B, and C & light chains on chromosome #15.
  • Function: Antigen recognition by T cells (specifically CD8 or T suppressor cells).
  • Purpose: Act as antigen presenting cells.

CLASS I MHC - COMPOSITION

  • Description: Comprised of 2 polypeptides:
    • Polymorphic heavy chain.
    • Non-polymorphic light chain (called B2 microglobulin).
  • Specific Alleles: HLA-A, HLA-B, HLA-C linked to white blood cells (WBC).

CLASS I MHC - DESCRIPTION

  • Allelic Forms: Many allelic forms of HLA-A, HLA-B, and HLA-C.
    • Alleles are numbered, given “W” designation when first identified in a workshop.
    • Expression: Co-dominantly expressed, meaning both alleles can be active.

CLASS II MHC GENES

  • Location: Chromosome #6, Region D at loci DR, DQ, DP.
  • Function: Antigen recognition by T helper cells.
  • Description: Comprised of 2 polypeptide chains called alpha and beta, which are polymorphic.

B-CELLS VS T-CELLS

  • Adaptive Antigen Recognition:
    • B-Cells: Recognize epitopes on intact antigens via receptors on B-cell surface (membrane-bound antibodies).
    • T-Cells: Recognize antigen fragments via T-cell receptors (TCR) that are complexed with unique proteins encoded by class I or class II MHC genes.
    • Class I MHC: Recognized by cytotoxic T-cells (CD8+).
    • Class II MHC: Recognized by helper T-cells (CD4+).

ANTIGEN RECOGNITION BY T-CELLS & B-CELLS

  • Lymphocytes:
    • B-cells recognize native antigens.
    • T-cells recognize processed antigens (fragmented).
  • Components:
    • MHC (major histocompatibility complex)
    • TCR (T-cell receptor)
    • APC (antigen presenting cells)
    • Antigen fragments.

CLASS III MHC GENES

  • Location: Situated in between Class I and Class II genes.
  • Function: Code for the production of complement proteins.

ADAPTIVE ANTIGEN RECOGNITION

What Happens?
  • Process:
    • Foreign antigen enters the body.
    • Phagocytosis occurs (macrophage ingests antigen).
    • Antigen is degraded and bound to MHC protein, then transported to cell surface.
    • Dendritic cells (APCs) are very effective at presenting antigens using MHC Class I or II.

ANTIGEN PRESENTATION PROCESS

  1. Antigen Entry: Antigen enters the dendritic cell.
  2. Degradation: Enzyme inside the cell breaks the antigen into smaller pieces.
  3. Binding: Antigen pieces bind to MHC protein inside the endoplasmic reticulum (ER).
  4. Transport: The MHC-antigen complex is transported to the cell surface via the Golgi apparatus.
  5. Presentation: The MHC protein presents the antigen on the surface of the cell membrane.

CLASS I AND CLASS II MHC PROTEINS

  • Class I MHC: Found on all nucleated body cells.
  • Class II MHC: Found only on antigen presenting cells (APCs), which include B-cells, macrophages, and dendritic cells.
  • Subtypes:
    • Cytotoxic T-cells (CD8) bind to Class I MHC.
    • Helper T-cells (CD4) bind to Class II MHC.

T-CELL ADAPTIVE AG RECOGNITION – CLASS I

  • Mechanism:
    • Class I HLA antigen binds with foreign antigen inside the rough ER.
    • The complex is then transported to the cell membrane.
    • Surface markers for antigen recognition appear on the cell membrane, recognized by cytotoxic T-cells (CD8).

T-CELL ADAPTIVE AG RECOGNITION – CLASS II

  • Mechanism:
    • Binding with foreign antigen occurs outside the rough ER in the endosomal compartment.
    • Recognized by helper T-cells (CD4).

INHERITANCE OF HLA ANTIGENS

Role in Inheritance
  • Inherit chromosome #6 from each parent, which bears 6 MHC genes per parent, forming a haplotype.
  • Genotype: Combination of inherited alleles from both parents.
  • Homozygous: Both chromosomes match (identical).
  • Heterozygous: Chromosomes are different.

ROLE OF HLA ANTIGENS

  • Alleles: Alternate forms of a gene existing at MHC loci.
    • MHC gene at A loci has 41 alleles.
    • MHC gene at B loci has 71 alleles.
  • Unique combination from different alleles provides each individual a unique genetic fingerprint.
  • Utilized in paternity testing to determine biological relationships.

HLA PATERNITY TESTING

Examples of Testing Results
  1. Example 1: Comparing shared HLA antigens between mother and child.
    • Results: Identifies possible father based on shared characteristics.
  2. Example 2: Evidence of exclusion based on mismatched antigens.
    • Direct Exclusion: Child has a trait neither parent possesses.
    • Indirect Exclusion: Child lacks a trait that must be inherited from the parent in question.
    • Inclusion: Child exhibits traits expected from the parent.

MHC GENES & DISEASES

  • Associations: Certain MHC gene variants correlated with diseases.
    • Example: HLA-B27 is linked to ankylosing spondylitis (a form of inflammatory disorder).
    • Example: HLA-DR4 is associated with rheumatoid arthritis.
    • Many autoimmune disorders are related to MHC gene variations.

MHC & TRANSPLANTATION DEFINITIONS

  • Types of Grafts:
    • Isografts: No genetic difference between donor and recipient (e.g., twins).
    • Allografts: Grafts between members of the same species.
    • Xenografts: Grafts across species (e.g., human to non-human).

GRAFT REJECTION

Types of Rejection
  • Hyperacute: Occurs minutes to hours post-graft.
  • Acute: Occurs weeks after transplantation.
  • Chronic: Occurs months or years after transplantation.
  • Notes: Patients receiving grafts typically remain on immunosuppressants to prevent graft rejection.

GRAFT VS HOST DISEASE (GvHD)

  • Definition: Occurs when donor cells attack recipient’s tissues, with T-cells in the graft recognizing the recipient as foreign.
  • Consequence: Can lead to severe immunocompromise in the recipient following the transplantation, especially in blood transfusions.