MHC class II

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(Redirected from
Major histocompatibility complex class II
)
MHC Class II
Schematic representation of MHC class II
Identifiers
SymbolMHC Class II
Membranome63

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

The

antigens presented by class II peptides are derived from extracellular proteins (not cytosolic as in MHC class I
).

Loading of a MHC class II molecule occurs by

cell surface
.

In humans, the MHC class II protein complex is encoded by the human leukocyte antigen gene complex (HLA). HLAs corresponding to MHC class II are HLA-DP, HLA-DM, HLA-DOA, HLA-DOB, HLA-DQ, and HLA-DR.

Mutations in the HLA gene complex can lead to bare lymphocyte syndrome (BLS), which is a type of MHC class II deficiency.

Structure

Like

heterodimers, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC.[1] The subdesignation α1, α2, etc. refers to separate domains within the HLA gene; each domain is usually encoded by a different exon within the gene, and some genes have further domains that encode leader sequences, transmembrane sequences, etc. These molecules have both extracellular regions as well as a transmembrane sequence and a cytoplasmic tail. The α1 and β1 regions of the chains come together to make a membrane-distal peptide-binding domain, while the α2 and β2 regions, the remaining extracellular parts of the chains, form a membrane-proximal immunoglobulin-like domain. The antigen binding groove, where the antigen or peptide binds, is made up of two α-helixes walls and β-sheet.[2]

Because the antigen-binding groove of MHC class II molecules is open at both ends while the corresponding groove on class I molecules is closed at each end, the antigens presented by MHC class II molecules are longer, generally between 15 and 24 amino acid residues long.

Expression

These molecules are constitutively expressed in professional, immune

monocytes which are MHC class II negative cells into functional APCs that express MHC class II on their surfaces.[4]

MHC class II is also expressed on group 3 innate lymphoid cells.

Importance

Having MHC class II molecules present proper peptides that are bound stably is essential for overall immune function.

[5] Because class II MHC is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood). Class II molecules interact mainly with immune cells, like the T helper cell (CD4+). The peptide presented regulates how T cells respond to an infection.[5] Stable peptide binding is essential to prevent detachment and degradation of a peptide, which could occur without secure attachment to the MHC molecule.[5] This would prevent T cell recognition of the antigen, T cell recruitment, and a proper immune response.[5] The triggered appropriate immune response may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells.

Synthesis

During synthesis of class II MHC in the endoplasmic reticulum, the α and β chains are produced and complexed with a special polypeptide known as the

invariant chain.[6]
The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to prevent it from binding cellular peptides or peptides from the endogenous pathway (such as those that would be loaded onto class I MHC).

The invariant chain also facilitates the export of class II MHC from the ER to the

cathepsins, leaving only a small fragment known as CLIP which maintains blockage of the peptide binding cleft on the MHC molecule. A MHC class II-like structure, HLA-DM, facilitates CLIP
removal and allows the binding of peptides with higher affinities. The stable class II MHC is then presented on the cell surface.

Recycling of MHC class II complexes

After MHC class II complexes are synthesized and presented on APCs they are unable to be expressed on the cell surface indefinitely, due to the internalization of the

dendritic cells can be recycled and developed into new MHC class II molecules plus peptide.[4]

Antigen processing and presentation

Unlike MHC I, MHC II is meant to present extracellular pathogens rather than intracellular. Furthermore, the first step is to acquire the pathogen through phagocytosis. The pathogen is then broken down in a lysosome and a desired component is then acquired and loaded onto a MHC II molecule. The MHC II molecule then travels to the surface to present the antigen to a helper T cell. MHC II active helper T cells which help release cytokines and other things which will help induce other cells which help to combat the pathogens outside the cells.

Genes

Alpha Beta
HLA-DM HLA-DMA HLA-DMB
HLA-DO HLA-DOA HLA-DOB
HLA-DP
HLA-DPA1
HLA-DPB1
HLA-DQ
HLA-DQA1, HLA-DQA2
HLA-DQB1, HLA-DQB2
HLA-DR HLA-DRA HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5

Pathways controlling MHC class II antigen presentation

Pathway: PSD4–ARL14/ARF7–MYO1E

Molecules involved

Several molecules are involved in this pathway.[7]

  • PIK3R2[8] and PIP5K1A[9] are two kinases that create substrates for PSD4.
  • PSD4[10][11] (Pleckstrin and Sec7 Domain containing 4) is a GEF (Guanine nucleotide Exchange Factor) that loads ARL14/ARF7 with GTP.
  • ARL14/ARF7[12] is a Small GTPase protein that is selectively expressed in immune cells. This protein is localized within MHC-II compartments in immature dendritic cells.
  • ARF7EP[13] is an effector of ARL14/ARF7 that interacts with MYO1E.
  • MYO1E[14] is a protein that controls MHC-II compartments with an actin-based mechanism.

Pathway

PIK3R2 and PIP5K1A are two

MHC-II loaded vesicles within the immature dendritic cell
, impeding its translocation to the cell membrane.

Picture showing PSD4–ARL14/ARF7–MYO1E Pathway.
Pathway showing how MHC-II distribution is controlled within Immature Dendritic Cells.

Bare lymphocyte syndrome

One type of MHC class II deficiency, also called bare lymphocyte syndrome, is due to mutations in the genes that code for transcription factors that regulate the expression of the MHC class II genes.

antibodies which are unable to perform as they are expected. The only current form of treatment is a bone-marrow transplant however even this does not cure the disease and most patients do not live past age ten.[17]

MHC class II and Type I diabetes

MHC class II genes and molecules are related to a multitude of different diseases, one of which being

Alleles of these genes that affect peptide binding to the MHC class II molecules seem to impact Type I diabetes risk the most. Specific allele polymorphisms have been identified to increase the risk (such as DRB1 and DQB1). Others have been associated with a resistance to the disease.[18]

See also

References

  1. ^ "Histocompatibility". Archived from the original on 2008-12-26. Retrieved 2009-01-21.
  2. S2CID 131777
    .
  3. .
  4. ^ .
  5. ^ .
  6. .
  7. .
  8. ^ "PIK3R2 phosphoinositide-3-kinase, regulatory subunit 2 (beta) [Homo sapiens (human)&#93". Entrez Gene.
  9. ^ "PIP5K1A phosphatidylinositol-4-phosphate 5-kinase, type I, alpha [Homo sapiens (human)". Entrez Gene.
  10. ^ PSD4 pleckstrin and Sec7 domain containing 4 [Homo sapiens (human)] - Gene - NCBI
  11. PMID 14662749
    .
  12. ^ "ARL14 ADP-ribosylation factor-like 14 [Homo sapiens (human)". Entrez Gene.
  13. ^ "ARL14EP ADP-ribosylation factor-like 14 effector protein [Homo sapiens (human)". Entrez Gene.
  14. ^ "MYO1E myosin IE [Homo sapiens (human)". Entrez Gene.
  15. PMID 17513710
    .
  16. .
  17. .
  18. .

External links