LEC 6 - MHC & TRANSPLANTATION IMMUNOLOGY

What do MHC genes encode?

Class I and Class II proteins essential for immune recognition

What is the MHC called in humans?

The Human Leukocyte Antigen (HLA) system

Why is it called the HLA system?

Because its gene products were originally identified on White Blood Cells (WBCs), or leukocytes

Where are MHC molecules generally found?

On all nucleated cells in the body

What pivotal role do MHC molecules play?

In the development of both humoral immunity (antibodies) and cellular immunity (T-cells)

How do RBCs and platelets possess HLA?

Although they are anucleated, they possess HLA because of their nucleated precursors

Where is the MHC/HLA genomic region located?

On the short arm of chromosome 6

What is the main function of MHC molecules?

To encode cell-surface antigens (Ag) that present antigen fragments to T cells

Why must antigen be combined with MHC molecules?

T-cell activation can only occur when antigen is presented on the cell surface by MHC molecules

What recognizes the MHC-Antigen complex?

T-Cell Receptors (TCRs) from the T cells

What is the result of T-Cell Receptor recognition of the complex?

The T-cell is activated to elicit an immune response

What are the main MHC Class I gene loci?

HLA-A, HLA-B, and HLA-C

How many genes encode a Class I molecule?

Each Class I molecule is encoded by a single gene

What is the chain structure of a Class I molecule?

It consists of an alpha-chain (or A-chain) and a β2​-microglobulin chain

Where are Class I molecules distributed (found) in the body?

On nucleated cells

Which immune cells do Class I molecules present antigen to?

Cytotoxic T cells (also known as CD8 cells)

What is the overall structure of a Class I MHC molecule?

A glycoprotein dimer made up of two noncovalently linked polypeptide chains

What are the two polypeptide chains that make up Class I MHC?

The alpha (α) chain and the β2​-microglobulin chain

How many domains does the α chain have?

Three domains: α1​, α2​, and α3​

How is the α chain anchored into the cell membrane?

Via a hydrophobic transmembrane segment

What is the critical role of β2​-microglobulin?

It is critical for the proper folding of the α chain

Which cell types exhibit the HIGHEST expression of Class I?

Lymphocytes and myeloid cells

Which cell types exhibit LOWER or UNDETECTED expression of Class I?

Liver hepatocytes, neural cells, muscle cells, and sperm

Which specific HLA Class I antigen is expressed at a much lower level than the others?

HLA-C antigens (compared to HLA-A and HLA-B)

What part of the MHC Class I molecule forms the peptide-binding site?

A deep groove at the top, formed by the α1​ and α2​ domains

What is the typical length of peptides that can be held by the Class I binding site?

Peptides that are 8 to 11 amino acids in length

Which regions of the Class I molecule exhibit the most polymorphism (variation)?

Primarily the α1​ and α2​ regions

Which regions of the Class I molecule are relatively constant?

The α3​ and β2​-microglobulin regions

What are the three nonclassical Class I antigens?

HLA-E, HLA-F, and HLA-G

Where are HLA-G antigens expressed?

On fetal trophoblast cells

What is the main role of HLA-G and HLA-E antigens?

To protect placental tissue from Natural Killer (NK) cells during the first trimester of pregnancy

What is the known function of HLA-F antigens?

Their function is currently unknown

What are the main MHC Class II gene loci?

HLA-DR, HLA-DQ, and HLA-DP

What is the chain structure of a Class II molecule?

It consists of two chains: an alpha (α) chain and a beta (β) chain

Where are Class II molecules primarily distributed (found)?

On Antigen-Presenting Cells (APCs), which include monocytes, macrophages, dendritic cells, and B cells

Which immune cells do Class II molecules present antigen to?

T-helper cells (also known as CD4+ cells)

What is the overall structure of major Class II molecules (DP, DQ, DR)?

They are heterodimers, consisting of two noncovalently bound polypeptide chains (α and β)

How many domains does each chain (α and β) have?

Two domains each

Which domains combine to form the peptide-binding site in Class II molecules?

The α1​ and β1​ domains

What is unique about the peptides bound by Class II molecules compared to Class I?

The binding site allows for longer peptides to be captured

Why are DR molecules highly polymorphic?

They possess numerous known alleles, contributing significantly to immune system diversity

How does the supply of DP molecules compare to DR molecules?

DP molecules are found in lower supply compared to DR

Which Class II molecule is the most highly expressed?

DR molecules are the most highly expressed

What are the additional class II genes (nonclassical class II genes)?

HLA-DM, HLA-DN, and HLA-DO

What is the function of the HLA-DM gene product?

It helps load peptides onto the major MHC Class II molecules

What is the function of the HLA-DO gene product?

It modulates (regulates) antigen binding to the major MHC Class II molecules

What is the known function of the HLA-DN gene product?

Its function is currently unknown

Where are the MHC Class III genes located?

Between the Class I and Class II regions on chromosome 6

What types of molecules do the Class III genes primarily code for?

Complement proteins and cytokines

Name some complement proteins coded by Class III genes

C4A, C4B, C2, and Factor B

What is a major cytokine coded by Class III genes?

Tumor necrosis factor (TNF)

Are Class III molecules expressed on the cell surface?

No. They are secreted proteins with immune function

Ankylosing Spondylitis

HLA B-27; Increased chance of cartilage inflammation and fusion in the spinal column

Hashimoto's Thyroiditis

HLA DR-5; Autoimmune disorder where antibodies destroy the thyroid gland

Rheumatoid Arthritis (RA)

HLA DR-4; Presence of antibodies against the cartilage of the joints

Multiple Sclerosis (MS)

HLA DR-2; Autoantibodies affect the myelin sheath of the nerve

Myasthenia Gravis

HLA DR-3; Antibodies attack Acetylcholine receptors at the neuromuscular junction

Systemic Lupus Erythematosus (SLE)

HLA DR-3; A multi-organ autoimmune disorder where autoantibodies attack the self

Type I Diabetes

HLA DR-3; Autoimmune disorder where antibodies attack the beta cells of the pancreas

Which type of transplant is associated with Graft-versus-Host Disease (GVHD)?

Bone marrow or stem cell transplants

Which type of transplant has the most risk of rejection (is most immunogenic)?

Skin transplants

Which type of transplant has a lower risk of rejection (is less immunogenic)?

Cornea transplants

What happens to grafts between genetically identical animals?

They are ACCEPTED

What happens to grafts between genetically non-identical animals?

They are REJECTED

Scenario: Recipient has 2 markers, Donor has 1.

Accepted

Scenario: Donor has 2 markers, Recipient has 2, but one marker is non-self.

Rejected

Autograft

Graft transferred from one position to another in the same individual (Graft from self)

Isograft / Syngraft

Graft transplanted between different but genetically identical recipient and donor (Graft from an identical twin)

Allograft

Graft between genetically different recipient and donor of the same species (Graft from anyone except an identical twin)

Xenograft

Graft between individuals of different species (e.g., a pig heart valve to a human heart)

What is the primary cause of FIRST-SET Rejection?

Activation of T-cell-Mediated Cellular Immunity

What process is characteristic of First-Set Rejection?

Sensitization occurs in the first few days, followed by mononuclear cell infiltration (few PMNs or plasma cells)

What is the typical outcome (timeline) for First-Set Rejection?

Graft is lost in 10 to 20 days

What is the primary cause of SECOND-SET Rejection?

Pre-existing sensitized lymphocytes from a prior exposure

What process is characteristic of Second-Set Rejection?

Accelerated rejection upon regrafting; transfer of sensitized lymphocytes speeds up the process

What is the typical outcome (timeline) for Second-Set Rejection?

Graft is rejected faster than the first set (usually in 3 to 5 days)

What is the definition of GVHD?

An immune-mediated condition where donor T lymphocytes attack the host's tissues

What key risk factor is associated with GVHD?

Occurs in immunocompromised or immunosuppressed recipients after blood transfusion or hematopoietic stem cell transplantation (HSCT)

What is the primary mechanism (Pathophysiology) of GVHD?

Donor T cells recognize recipient antigens as foreign and initiate an immune attack

What determines the severity of GVHD?

The severity depends on the host's immunodeficiency, not the donor lymphocyte count

What is the typical ONSET for ACUTE GVHD?

Within 3 months post-transplant, or 3-30 days post-transfusion

What are the KEY FEATURES of ACUTE GVHD?

Rash (often on palms, soles), diarrhea, abdominal pain, jaundice, fever, and interstitial pneumonia

What is the typical ONSET for CHRONIC GVHD?

Greater than 100 days (usually months to years) post-transplant

What are the KEY FEATURES of CHRONIC GVHD?

Scleroderma-like skin changes, cholestatic liver disease, and increased infections