Major Histocompatibility Complex (MHC) Class II System

The MHC Class II system is a key component of the adaptive immune response, specialized in presenting extracellular antigens to CD4+ helper T cells. This system is essential for initiating immune responses against pathogens that reside outside host cells, such as bacteria, fungi, and parasites, as well as for orchestrating humoral immunity via B cell activation.

---

1. Structure of MHC Class II Molecules

MHC Class II molecules are heterodimers, consisting of two polypeptide chains:

1. α (alpha) chain:

   • Encoded by HLA-DP, HLA-DQ, or HLA-DR in humans.

   • Composed of α1 and α2 extracellular domains, a transmembrane segment, and a short cytoplasmic tail.

   • The α1 domain contributes to the peptide-binding groove.

2. β (beta) chain:

   • Also encoded by HLA-DP, DQ, or DR loci.

   • Composed of β1 and β2 extracellular domains, transmembrane segment, and cytoplasmic tail.

   • The β1 domain forms the other half of the peptide-binding groove.

• Peptide-binding groove: Formed by the α1 and β1 domains.

  • Unlike MHC Class I, the groove is open at both ends, allowing binding of longer peptides (typically 13–25 amino acids).

  • Peptide binding is stabilized by multiple hydrogen bonds and anchor residues, but the system tolerates greater length and sequence variability.

---

2. Expression of MHC Class II

• Restricted expression: MHC Class II molecules are expressed primarily on professional antigen-presenting cells (APCs):

  • Dendritic cells

  • Macrophages

  • B lymphocytes

• Inducible expression: Non-APCs can express MHC Class II in response to cytokines, especially interferon-gamma (IFN-γ).

• Polymorphism:

  • MHC Class II genes are highly polymorphic.

  • Variability in α and β chains determines which peptides can be presented and influences susceptibility to autoimmune diseases.

---

3. Antigen Processing and Presentation Pathway

MHC Class II presents exogenous antigens, which are internalized by APCs through phagocytosis, endocytosis, or pinocytosis. The pathway includes:

Step 1: Antigen Uptake

• APCs engulf pathogens or extracellular proteins.

• Vesicles (endosomes or phagosomes) contain the ingested material.

Step 2: Proteolytic Processing

• Acidification and lysosomal proteases degrade the proteins into peptide fragments of suitable length (13–25 amino acids).

Step 3: Synthesis and Transport of MHC Class II

• Newly synthesized MHC Class II α and β chains assemble in the endoplasmic reticulum.

• The invariant chain (Ii) binds to the peptide-binding groove:

  • Blocks premature peptide binding.

  • Directs MHC II to endosomal/lysosomal compartments.

Step 4: Peptide Loading

• In the acidic vesicle, the invariant chain is degraded, leaving a fragment called CLIP (Class II-associated invariant chain peptide) in the groove.

• HLA-DM (a chaperone protein) catalyzes the removal of CLIP and facilitates the binding of antigenic peptides to the MHC Class II molecule.

Step 5: Surface Expression

• The peptide-MHC Class II complex is transported to the cell surface, where it can be recognized by CD4+ T cells.

---

4. Interaction with CD4+ Helper T Cells

• Recognition: T cell receptor (TCR) on CD4+ helper T cells binds the peptide-MHC II complex.

• Co-receptor: CD4 binds to the β2 domain of MHC II, stabilizing the interaction.

• Activation: If the peptide is non-self:

  • T cells secrete cytokines (IL-2, IL-4, IFN-γ, etc.).

  • This promotes clonal expansion, B cell activation, and macrophage activation.

• Outcome: MHC Class II presentation initiates:

  • Humoral immunity: Activation of B cells and antibody production.

  • Cell-mediated immunity: Activation of macrophages and coordination of immune responses.

---

5. MHC Class II and Immune Regulation

MHC Class II molecules are pivotal in:

1. Self vs. non-self recognition

   • APCs present processed antigens to CD4+ T cells, which decide whether to initiate an immune response.

2. Tolerance

   • During thymic selection, MHC Class II mediates positive and negative selection of CD4+ T cells.

   • Defects can lead to autoimmunity or immunodeficiency.

3. Disease association

   • Certain MHC II alleles are linked to autoimmune diseases:

     • HLA-DR3/DR4 → Type 1 diabetes

     • HLA-DR2 → Multiple sclerosis

     • HLA-DQ2/DQ8 → Celiac disease

---

6. Differences Between MHC Class I and II

---

7. Clinical Relevance

1. Autoimmunity

   • Mis-presentation of self-antigens via MHC Class II can trigger autoimmune diseases.

2. Infections

   • Efficient antigen presentation is essential for clearance of extracellular bacteria (e.g., Mycobacterium tuberculosis).

3. Transplantation

   • HLA Class II matching is critical in organ and bone marrow transplantation to reduce graft rejection.

4. Immunodeficiencies

   • Bare Lymphocyte Syndrome (BLS) Type II: Genetic defect in MHC Class II expression → severe immunodeficiency with recurrent infections.

---

8. Summary

• MHC Class II molecules are heterodimeric proteins that present extracellular-derived peptides to CD4+ T helper cells.

• Expression is restricted to professional APCs, but can be induced in other cells by cytokines.

• Antigen processing involves internalization, proteolysis, invariant chain-mediated trafficking, and HLA-DM-facilitated peptide loading.

• MHC Class II is polymorphic, enabling diverse peptide presentation and influencing autoimmunity, infection susceptibility, and transplant compatibility.

• Recognition by CD4+ T cells leads to activation of humoral and cell-mediated immune responses, making MHC Class II a central component of adaptive immunity.

---

In essence, while MHC Class I protects against intracellular threats, MHC Class II coordinates the immune defense against extracellular pathogens and orchestrates broader immune responses through helper T cells.