View source for MHC class II

{{Short description|Protein of the immune system}}
{{Infobox protein family
| Symbol = MHC Class II
| Name = MHC Class II
| image = MHC Class 2.svg
| width =
| caption = Schematic representation of MHC class II
| InterPro= 
| PROSITE = 
| SCOP = 
| TCDB =
| OPM family=
| OPM protein=
| Pfam= 
| PDB=
| Membranome superfamily= 63
}}
'''MHC Class II molecules''' are a class of [[major histocompatibility complex]] (MHC) molecules normally found only on [[antigen-presenting cell#Types and functions|professional antigen-presenting cell]]s such as [[dendritic cell]]s, [[Macrophage|macrophages]], some [[endothelium|endothelial cell]]s, [[thymic epithelial cell]]s, and [[B cell]]s. These cells are important in initiating [[Immune response|immune responses]].

[[Antigens]] presented by MHC class II molecules are exogenous, originating from extracellular proteins rather than cytosolic and endogenous sources like those presented by [[MHC class I]].

The loading of a MHC class II molecule occurs by [[phagocytosis]]. Extracellular proteins are [[endocytosis|endocytosed]] into a [[phagosome]], which subsequently fuses with a [[lysosome]] to create a [[phagolysosome]]. Within the phagolysosome, lysosomal enzymes degrade the proteins into [[peptide fragment]]s. These fragments are then loaded into the peptide-binding groove of the MHC class II molecule. Once loaded, the MHC class II-peptide complexes are transported to the [[plasma membrane]] via [[vesicular transport]], where they present the [[antigens]] to the extracellular environment.<ref>{{cite journal |last1=Rock |first1=Kenneth L. |last2=Reits |first2=Eric |last3=Neefjes |first3=Jacques |title=Present Yourself! By MHC Class I and MHC Class II Molecules |journal=Trends in Immunology |date=November 2016 |volume=37 |issue=11 |pages=724–737 |doi=10.1016/j.it.2016.08.010|pmc=5159193 }}</ref>

In humans, the MHC class II protein complex is encoded by the [[human leukocyte antigen|human leukocyte antigen gene complex (HLA)]]. Class II HLAs are composed of the classical [[HLA-DP]], [[HLA-DQ]], and [[HLA-DR]] and non-classical [[HLA-DM]] and [[HLA-DO]] MHC molecules. 


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

== Structure ==
Like [[MHC class I]] molecules, class II molecules are also [[heterodimer]]s, but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC.<ref name="urlHistocompatibility">{{cite web |url=http://www.cehs.siu.edu/fix/medmicro/mhc.htm |title=Histocompatibility |access-date=2009-01-21 |url-status=dead |archive-url=https://web.archive.org/web/20081226224824/http://www.cehs.siu.edu/fix/medmicro/mhc.htm |archive-date=2008-12-26 }}</ref> The subdesignation α1, α2, etc. refers to separate domains within the [[human leukocyte antigen|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.<ref name="pmid16557259">{{cite journal | vauthors = Jones EY, Fugger L, Strominger JL, Siebold C | title = MHC class II proteins and disease: a structural perspective | journal = Nature Reviews. Immunology | volume = 6 | issue = 4 | pages = 271–82 | date = April 2006 | pmid = 16557259 | doi = 10.1038/nri1805 | s2cid = 131777 }}</ref>

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 [[antigen-presenting cell]]s, but may also be induced on other cells by [[interferon γ]].<ref name=PMID11983150>{{cite journal | vauthors = Ting JP, Trowsdale J | title = Genetic control of MHC class II expression | journal = Cell | volume = 109 Suppl | issue = 2 | pages = S21-33 | date = April 2002 | pmid = 11983150 | doi = 10.1016/s0092-8674(02)00696-7 | doi-access = free }}</ref> They are expressed on the epithelial cells in the thymus and on APCs in the periphery. MHC class II expression is closely regulated in APCs by [[CIITA]], which is the MHC class II transactivator. CIITA is solely expressed on professional APCs; however, non-professional APCs can also regulate CIITA activity and MHC II expression. As mentioned interferon&nbsp;γ  (IFN&nbsp;γ) triggers the expression of CIITA and is also responsible for converting [[monocytes]] which are MHC class II negative cells into functional APCs that express MHC class II on their surfaces.<ref name="Roche_2015">{{cite journal | vauthors = Roche PA, Furuta K | title = The ins and outs of MHC class II-mediated antigen processing and presentation | journal = Nature Reviews. Immunology | volume = 15 | issue = 4 | pages = 203–16 | date = April 2015 | pmid = 25720354 | doi = 10.1038/nri3818 | pmc = 6314495 }}</ref>

MHC class II is also expressed on group 3 [[innate lymphoid cell]]s.

== Importance ==
Having MHC class II molecules present proper peptides that are bound stably is essential for overall immune function.<ref name="Kuby_2013">{{cite book | first1 = Judith A | last1 = Owen | first2 = Jenni | last2 = Punt | first3 = Sharon A | last3 = Stranford | first4 = Patricia P | last4 = Jones | first5 = Janis | last5 = Kuby | name-list-style = vanc |title= Kuby Immunology |publisher=W H Freeman & Co |isbn=978-1-4641-1991-0 |edition=7th | date = 2013 |location=New York |oclc=820117219}}</ref>  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|CD4<sup>+</sup>]]). The peptide presented regulates how T&nbsp;cells respond to an infection.<ref name="Kuby_2013" /> Stable peptide binding is essential to prevent detachment and degradation of a peptide, which could occur without secure attachment to the MHC molecule.<ref name="Kuby_2013" /> This would prevent T cell recognition of the antigen, T cell recruitment, and a proper immune response.<ref name="Kuby_2013" /> 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 cell]]s.

==Synthesis==
{{More citations needed section|date=June 2020}}
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]].<ref>{{Cite journal|last=Cresswell|first=Peter|date=1996-02-23|title=Invariant Chain Structure and MHC Class II Function|journal=Cell|language=English|volume=84|issue=4|pages=505–507|doi=10.1016/S0092-8674(00)81025-9|issn=0092-8674|pmid=8598037|s2cid=8199773 |doi-access=free}}</ref> 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 [[Golgi apparatus]], followed by fusion with a late endosome containing endocytosed, degraded proteins. The invariant chain is then broken down in stages by proteases called [[cathepsins]], leaving only a small fragment known as [[CLIP (protein)|CLIP]] which maintains blockage of the peptide binding cleft on the MHC molecule. A MHC class II-like structure, [[HLA-DM]], facilitates [[CLIP (protein)|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 [[plasma membrane]] by the APCs(antigen presenting cells). In some cells, antigens bind to recycled MHC class II molecules while they are in the early [[endosomes]], while other cells such as dendritic cells internalize antigens via receptor-mediated endocytosis and create MHC class II molecules plus peptide in the endosomal-lysosomal antigen processing compartment which is independent of the synthesis of new MHC class II complexes. These suggest that after the antigen is internalized, already existent MHC class II complexes on mature [[dendritic cells]] can be recycled and developed into new MHC class II molecules plus peptide.<ref name="Roche_2015"/>

== 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 [[T helper cell|helper T&nbsp;cell]]. MHC II activates helper T&nbsp;cells which help release cytokines and other things which will help induce other cells which help to combat the pathogens outside the cells.

==Genes==
{| class="wikitable"
| ''' ''' || '''Alpha''' || '''Beta''' 
 |- 
 | [[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]] 
 |- 
 | [[HLA-DM]] || [[HLA-DMA]]|| [[HLA-DMB]] 
 |- 
 | [[HLA-DO]] || [[HLA-DOA]]|| [[HLA-DOB]] 
|}

==Pathways controlling MHC class II antigen presentation==

=== Pathway: PSD4–ARL14/ARF7–MYO1E ===

==== Molecules involved ====

Several molecules are involved in this pathway.<ref>{{cite journal | vauthors = Paul P, van den Hoorn T, Jongsma ML, Bakker MJ, Hengeveld R, Janssen L, Cresswell P, Egan DA, van Ham M, Ten Brinke A, Ovaa H, Beijersbergen RL, Kuijl C, Neefjes J | title = A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation | journal = Cell | volume = 145 | issue = 2 | pages = 268–83 | date = April 2011 | pmid = 21458045 | doi = 10.1016/j.cell.2011.03.023 | doi-access = free }}</ref>

*'''PIK3R2<ref>{{cite web | title = PIK3R2 phosphoinositide-3-kinase, regulatory subunit 2 (beta) [Homo sapiens (human)&#93 | url = https://www.ncbi.nlm.nih.gov/gene/5296 | work = Entrez Gene }}</ref>''' and '''PIP5K1A<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/8394 | title = PIP5K1A phosphatidylinositol-4-phosphate 5-kinase, type I, alpha [Homo sapiens (human) | work = Entrez Gene }}</ref>''' are two kinases that create substrates for PSD4.
*'''PSD4<ref>[https://www.ncbi.nlm.nih.gov/gene/23550 PSD4 pleckstrin and Sec7 domain containing 4 [Homo sapiens (human)&#93; - Gene - NCBI<!-- Bot generated title -->]</ref><ref>{{cite journal | vauthors = Prigent M, Dubois T, Raposo G, Derrien V, Tenza D, Rossé C, Camonis J, Chavrier P | title = ARF6 controls post-endocytic recycling through its downstream exocyst complex effector | journal = The Journal of Cell Biology | volume = 163 | issue = 5 | pages = 1111–21 | date = December 2003 | pmid = 14662749 | pmc = 2173613 | doi = 10.1083/jcb.200305029 }}</ref>''' ('''P'''leckstrin and '''S'''ec7 '''D'''omain containing '''4''') is a [[Guanine nucleotide exchange factor|GEF]] ('''G'''uanine nucleotide '''E'''xchange '''F'''actor) that loads ARL14/ARF7 with GTP.
*'''ARL14/ARF7<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/80117 | title = ARL14 ADP-ribosylation factor-like 14 [Homo sapiens (human) | work = Entrez Gene }}</ref>''' is a [[Small GTPase]] protein that is selectively expressed in immune cells. This protein is localized within MHC-II compartments in immature [[dendritic cell]]s.
*'''ARF7EP<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/120534 | title = ARL14EP ADP-ribosylation factor-like 14 effector protein [Homo sapiens (human) | work = Entrez Gene }}</ref>''' is an effector of ARL14/ARF7 that interacts with [[MYO1E]].
*'''MYO1E<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/4643 | title = MYO1E myosin IE [Homo sapiens (human) | work = Entrez Gene }}</ref>''' is a protein that controls MHC-II compartments with an actin-based mechanism.

==== Pathway ====

PIK3R2 and PIP5K1A are two [[kinases]] that phosphorylate [[Phosphatidylinositol]] (PIP) providing PSD4 with substrates for its GTP loading ability. PSD4 as a [[guanine exchange factor]], loads ARL14/ARF7 with GTP. Subsequently, ARF7EP interacts with [[MYO1E]] which binds itself to [[actin]] myofibers. Altogether, this complex contributes to maintain [[MHC-II]] loaded vesicles within the immature [[dendritic cell]], impeding its translocation to the cell membrane.

[[File:PSD4.ARL14.MYO1E PATHWAY.jpg|thumb|center|alt=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.<ref name="pmid17513710">{{cite journal | vauthors = Steimle V, Otten LA, Zufferey M, Mach B | title = Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). 1993 | journal = Journal of Immunology | volume = 178 | issue = 11 | pages = 6677–88 | date = June 2007 | pmid = 17513710 }}</ref> It results in the depletion of [[CD4]] T cells and some immunoglobulin isotypes even though there are normal levels of both [[CD8]] T cells and [[B cells]] present. Deficient MHC class II molecules are unable to present antigens to T cells and properly activate T cells. T cells are then unable to proliferate and secrete [[cytokines]] which normally participate in the immune response. Not only do the deficient MHC class II molecules affect the activation and proliferation of T cells but also the rest of the immune response cascade which includes B cells. Therefore, with this decrease in the number of T cells, the T cells cannot interact and activate the B cells. Normally when B cells are activated they divide, proliferate and differentiate, which includes the differentiation of these cells into plasma cells which are responsible for producing antibodies.<ref>{{cite book |last1=Mak |first1=Tak W. |first2=Mary E. | last2 = Saunders | name-list-style = vanc |title=The immune response basic and clinical principles |date=2006 |publisher=Elsevier/Academic |location=Amsterdam |isbn=978-0-12-088451-3 | oclc = 986987876 }}</ref> However, when there is a deficiency in MHC class II molecules B cells are not activated and cannot differentiate into [[plasma cells]] which causes them to be deficient in [[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.<ref name="pmid17349258">{{cite journal | vauthors = Serrano-Martín MM, Moreno-Pérez D, García-Martín FJ, Jurado-Ortiz A | title = [Major histocompatibility complex class II deficiency] | language = es| journal = Anales de Pediatria | volume = 66 | issue = 3 | pages = 305–8 | date = March 2007 | pmid = 17349258 | doi = 10.1157/13099694}}</ref>

==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 [[Type I diabetes]]. HLA class II genes are the most important genes associated with the risk of inheriting Type I diabetes, accounting for about 40-50% of [[heritability]]. [[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 [[gene polymorphism|polymorphisms]] have been identified to increase the risk (such as DRB1 and DQB1).  Others have been associated with a resistance to the disease.<ref name="pmid24752371">{{cite journal | vauthors = Xie Z, Chang C, Zhou Z | title = Molecular mechanisms in autoimmune type 1 diabetes: a critical review | journal = Clinical Reviews in Allergy & Immunology | volume = 47 | issue = 2 | pages = 174–92 | date = October 2014 | pmid = 24752371 | doi = 10.1007/s12016-014-8422-2 | s2cid = 26085603 }}</ref>

== See also ==
* [[Cross-presentation]]
* [[Bare lymphocyte syndrome]]

== References ==
{{Reflist|2}}

== External links ==
* {{MeSH name|Histocompatibility+Antigens+Class+II}}
* {{MeSH name|MHC+Class+II+Genes}}
{{Immunoglobulin superfamily immune receptors}}
{{Surface antigens}}

[[Category:Genes]]
[[Category:Immune system]]
[[Category:Glycoproteins]]
[[Category:MHC class II| ]]