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MHC PROTEINS
     The immune responses of the vertebrates in the first two pictures differs from the invertebrates in the second two pictures.  One of the traits of the vertebrates which makes the vertebrate-specific acquired immunity possible. 
TURTLE
DRAGONFLY BUTTERFLY
     Acquired immunity is only found in vertebrates and depends on B and T cell receptors.  While the immunoglobulin receptors on B cells can recognize proteins, receptors on T cells recognize peptides which are attached to MHC molecules.   In general, MHCI proteins (composed of MHCIa and b2microglobulin chains) bind peptides in the cytoplasm.  These peptides are produced when proteins are broken down in the cytoplasm and taken to the endoplasmic reticulum where they bind the MHC proteins.  The MHC I proteins “present” these peptides on the cell membrane, predominantly to cytotoxic T cells. 
MHC VIRUS CELL
PRESENTING
MHCII proteins (which are heterodimers composed of a and b chains) bind peptides in lysosomes and endosomes.  These peptides are typically obtained from the breakdown of foreign proteins, originating outside the cell.  MHCII proteins present their peptides to T Helper cells.   The MHC proteins are encoded by HLA genes (human leukocyte antigens) and have changed little in structure during their evolution.  b2 microglobulin can function by itself as a chemotactic factor and may have evolved before the MHC proteins. 
     Although higher vertebrates define “self” through the use of MHC proteins and their interactions with T cells and Natural Killer cells, distinguishing between self and non-self seems to be a characteristic of all animals.  Sponges can distinguish between self and non-self in that a sponge can reject a graft made from another sponge.  Cnidarians can also distingiush between self and nonself (Cadavid, 2004).  Urochordates can distinguish between self and nonself and reject grafts by using a variety of elements of their innate immunity mechanisms (such as complement, apoptosis, proteasome, cytokine, and pattern recognition proteins) (Oren, 2007). Sea anemone cells are depicted below.
ANENOME

Some T lymphocytes called natural killer T cells (which express proteins typical of both NK cells and T cells) respond to lipids and glycolipids bound to MHC protein CD1d (rather than peptides). They are produced in the thymus and seem to bridge functional aspects of the innate and adaptive immune responses (Kaer, 2007).

1)     MHC

     There is a very large block of genes on human chromosome 6 known as the Major Histocompatibility Complex which comprises about 0.1% of the genome (Yu, 2000).  The MHC complex has more than 224 genes and more than 100 disorders are associated with this region (Anzai, 2003).  The genes in this region include many of the elements essential for both adaptive and innate immunity.  These genes determine the ability of an organ recipient to accept a donated organ and a number of autoimmune diseases map to this region (representing the majority of the diseases which map to this region).  For example, although the genes which determine the chronic inflammatory disorder multiple sclerosis are not known, a number of genes in the MHC seem to be involved (‘t Hart, 2001).  The large number of genes in the MHC I and II regions, like the antibody and TCR genes, originated through the repeated duplication of ancestral genes rather than gene conversion (Nei, 1997).

     One of the many interesting features of the MHC complex is the polymorphism which exists at many of the loci.  Unlike most genes in the genomes, there appears to be a selective pressure to create variation in these genes and most alleles differ by multiple nucleotides.  Individual MHC genes may exist with more than 100 alleles in some species and are the most polymorphic vertebrate genes known (Penn, 1998). Some MHC genes have more than 400 alleles (Anzai, 2003).  More than 1500 alleles of the HLA genes in the MHC and the most common changes from ancestral alleles are in the peptide binding regions where there are more nonsynonomous substitutions than synonomymous (OMIM; Reche, 2003). Many of the MHC genes are linked and are thus inherited as a block unit, or haplotype (Penn, 1998).

     The genes of MHC I and II are immunoglobulins which are most similar to antibodies and T cell receptors (TCR).  MHC proteins have 4 external domains, two of which are part of the immunoglobulin family only found in B and T cells.  The other two form the peptide binding pocket (Flajnik, 1991).  The ancestral MHC is likely to have been duplicated to produce MHC class I and class II regions; MHC I and II are almost identical in their tertiary structures.  Additional duplications and modifications have occurred since this original duplication to produce the different MHC I and II genes (Gaudieri, 1999; Ohta, 2000).  Echinoderms possess proteins which have similar structure and some sequence homology to antibodies, T cell receptors, and MHC proteins (Hibino, 2006). Although they lack MHC genes, urochordates possess a region which seems to be ancestral to the multiple MHC regions which resulted from the genome duplications in early vertebrates (Kasahara, 2004).  MHC genes themselves seem to have arisen with the in the evolution of the gnathostomes, coinciding with the proposed rounds of genome duplication which seem to have occurred at the base of this group (Ohta, 2000; Bartyl, 1994).  

    Cartilaginous fish have 3 types of MHC molecule (MHCIa, MHCIIa, and MHCIIb) despite the fact that they do not have T cells.   (Berstein, 1996; Kasahara, 1992).  Unlike the bony fish in which the MHC I and II genes are separated (and thus are referred to as MH genes), MHC genes exist in large complexes of linked genes in cartilaginous fish and tetrapods, indicating that this was probably the condition in ancestral gnathostomes (Dixon, 2001).  The MHC molecules in coleocanths possess a similar intron-exon organization compared to those in mammals and are very similar to those of amphibians (Betz, 1994).   Humans and mice share hypervariable regions in MHC molecules (Lundberg, 1992).  In mammals, the class I and class II genes are in four paralogous clusters (Ohta, 2000). 

     The MHC I and MHC II genes encode 2  chain glycoproteins. MHC Class I and II receptors differ in both their structure and specificity.  Class I molecules consist of a heavy chain with 3 MHC domains and β2 while Class II consist of α and β chains which are noncovalently linked (Dixon, 2001). Class I bind endogenous peptides 8-10 amino acids from intracellular pathogens and interact with CD8 T cells (Reche, 2003).  Class II bind exogenous peptides of 9-22 amino acids from extracellular pathogens and interact with CD4 T cells (Reche, 2003; Dixon, 2001).  MHC Class III molecules involved in immune system but are not immunglobulins, nor are they related to MHC I and II molecules (Reche, 2003).

     The primate MHC Complex (HLA locus) is composed of three class MHC Ia loci (HLA-A, HLA-B, and HLA-C), a number of class MHC Ib loci (including HLA-E, HLA-F, HLA-G, HLA-H, and HLA-J), and class MHC II loci which form four families (HLA-DO, HLA-DP, HLA-DQ, and HLA-DR) (Kreiner, 2001).  There are 4 major genes: HLA-A, HLA-B, HLA-C (which produce MHC I chains) and HLA-DR (which produces MHC II chains) (OMIM). Just after the ape lineage separated from the Old World monkey lineage, the MHC-B region duplicated in apes to produce the MHC-B and MHC-C regions. Subsequently, a duplication in the MIC (MHC class I chain-related molecule) region produced MIC-A and MIC-B regions (Fukami-Kobayashi, 2005). The genes of the MHC class I group are shared between humans and other primates (although MHC-C seems to have arisen as a duplicate of MHC-B in ancestral apes) (Bontrop, 2006).

     Humans have at least 20 MHCIa genes and five pairs of MHCIIa and MHCIIb genes.  This number may be limited due to the involvement of the MHC proteins in the negative selection of T cells to prevent reactions against self.  The more MHC proteins an organism has, the more T cells would be selected against.  Even polyploid animals usually only express a diploid set of MHC proteins (OMIM).

 Xenopus ruwensoriensis possesses 108 chromosomes (which, given that Xenopus laevis possesses 36 chromosomes, indicates that much of the genome has been duplicated at least once) but still only expressed 2 MHC haplotypes like its diploid relative (Flajnik, 1991).

PRESENTING

MHC I. CLASS Ia

The Ia set of MHC genes are known as classical loci and are the major determinants of antigen presentation.  Classical MHC proteins are present in bony fish and are expressed on similar cell types as those in higher vertebrates (Dijkstra, 2003).  They are expressed in all cells which have nuclei and are highly polymorphic.  In the peptide binding region of Class Ia genes, the rate of nonsynonymous substitution exceeds the rate of synonymous substitution, indicating that polymorphism in this site gives advantages to heterozygotes.  It is thought that the different MHC alleles in heterozygotes are capable of presenting a greater diversity of potential pathogen peptides and thus give heterozygotes an advantage in fighting microbes (Hughes, 1999).  Molecular analyses indicate how point mutations and splicing variations could have produced human HLA alleles from those of non-humans (Roman, 2007).

MHC 1

MHC Ia

HLA-A

     The HLA-A gene is important for determining organ donors.

 

HLA-B

   A number of B alleles are of clinical significance.  The allele B53 offers resistance to malaria (B alleles can offer as much resistance to malaria as the sickle hemoglobin allele).  B8 is associated with an increased susceptibility to pulmonary tuberculosis and B53 with an increased susceptibility to HIV.  The B57 allele offers resistance to HIV (OMIM).

 

HLA-C

 

MHC I. CLASS Ib

Class Ib genes are related to Class Ia genes but lack the selection for polymorphism observed in MHC Class Ia molecules and are expressed only in certain tissues.  The Class Ib genes seem to have diverged after the separation of the orders of placental mammals.   Some Class Ib genes seem to be once widely expressed Class Ia genes that changed their expression pattern after mutations in their regulatory regions.  As a result, the Class Ia genes in one species may be more closely related to Class Ib genes than Class Ia genes in another species (as in the case of MHC-G).  Some feel that Class Ib genes may represent ancestral genes which are in the process of being lost (Hughes, 1999).

 

HLA-E, F, and G are less polymorphic than the other HLA genes.

 HLA-E and HLA-F are non-classical MHC class Ib member. All cells with nuclei express HLA-E which presents to cytotoxic T cells. HLA-E is the most divergent gene among the MHC I group.  It seems that it interacts with the natural killer cell receptor CD94/NK62A.    Natural Killer cells kill cells which lack HLA-E.  TCR receptors of CD8 cells with NK like activity interact with HLA-E receptors in the lysis of tumor cells (Moretta, 2002; Moscoso, 2006).

HLA-F is expressed on B cells and some cells throughout the lymphatic system. Both have very low polymorphism levels and both are expressed in the fetal placenta towards the end of gestation (Moscoso, 2006).

 

 

HLA-F no longer seems to be necessary for normal development.  Ancient duplications of this gene gave rise to the genes HLA-G and MICE.

 

HLA-G

Although similar to class Ia genes, there is a stop codon in exon 6 of higher ape MHC-G genes which prevents the translation of most of exon 6 in addition to exons 7 and 8. The soluble alternate transcripts retain a part of intron 4 contain a stop codon which prevents the translation of the transmembrane regions (Castro, 2000a).

     HLA-G is the only MHC protein expressed in the trophoblast of the placenta where it interacts with the maternal natural killer cells by interacting with the Natural Killer inhibitory receptors NKIR1 and NKIR2 (and perhaps a third receptors as well).  This interaction prevents the maternal natural killer cells from attacking the fetus (producing the maternal-fetal tolerance on which the development of placental mammals depends).  Mother-fetus tolerance is created by a number of factors including HLA-G decrease of NK activity, regulation of complement proteins, regulation of T cell proliferation. Interestingly, HLA-G is the predominant HLA gene in New World monkeys.  MHC-G can be spliced to produce a number of alternate transcripts (HLA-G1 through 6) (Arnaiz-Villena, 1999; OMIM; Castro, 2000a; Golos, 2003).  In rhesus monkeys, HLA-G is a pseudogene but another molecule HLA-AG (similar to HLA-A) functions similarly (Golos, 2003).

     In New World monkeys, MHC-G proteins seem to present antigens rather than the MHC-A and MHC-B proteins as in catarrhine primates.  With the exception of possible MHC-C, MHC-G proteins are the only class I MHC proteins produced in New World monkeys.  The number of functional alleles of the MHC-G varies in different primate groups: there are the highest number of alleles in New World monkeys, less in Old World monkeys, and the greatest invariance in apes, especially humans.  The selection for this invariance may be related to the increased length of pregnancy in apes and humans (Arnaiz-Villena, 1999).  MHC-G homologs are known in mice.  MHC-G may be the ancestral class I gene(Arnaiz-Villena, 1999).  There is a 51 base pair deletion in exon 8 of the MHC-G gene which is shared by apes but not OW monkeys (Castro, 2000).

 

     There are at least 12 pseudogenes known in the MHC I region; some are full length pseudogenes while others have partial deletions (OMIM), including HLA-H, HLA-J, HLA-K, and HLA-L.  The HLA-H pseudogene is homologous to a functional gene in gorillas.  Human pseudogenes HLAS-COQ and HLA-DEL also are homologous to functional genes in gorillas (Golos, 2003).  The MHC I region contains 4 pseudogenes which are similar to the classical rather than the nonclassical HLA genes (Geraghty, 1992).  The human MHCI complex includes a gene HLA-AR which is similar to the antigen presenting HLA-A locus but which has been inactivated by several mutations.  It may be a remnant of an ancestral antigen presenting system (Zemmour, 1990).

 

 

 

MHC I. CLASS Ic

Class Ic genes consist of MIC genes (A through E, of which only A and B are expressed ) and the hemachromatosis candidate gene, Hfe.  Sequence comparisons indicate that Class Ic genes diverged before the separation of therian mammals (Hughes, 1999).   MICA interacts with T cells but it does not require β2-microglobulin or bound peptides to be present on cell membranes (Hughes, 1999). 

 

MHCI-like Sequences (HLALS genes)

     There are a number of genes of the MHC I gene family which perform a diversity of functions.

--CD1

--zinc a2 glycoprotein

--MICA and MICB

--These polymorphic genes produce proteins which protect the intestinal tract.  MICA proteins bind NKG20 on gamma/delta T cells, CD8 T cells, and natural killer cells to start cell lysis; this process is involved in tumor suppression.  MICA and MICB are involved with the stress induced interaction between epithelial cells of the skin and intestine and gamma/delta T cells.

 

--The Fc receptor has been shown to uptake IgG from maternal milk in the intestines of mice.

 

Some class Ib-related genes are not located within the Major Histocompatibility Complex.  These Class Id genes include FcRn, Zinc α2-glycoprotein, MRI, and CD1.  The five human CD1 genes seem to bind lipids rather than peptides.  FcRn can transport antibodies across epithelia.  This group of genes also seems to have diverged before the split of placental orders (Hughes, 1999)..

 

 

b2 microglobulin

     This molecule is more closely related to the immunoglobulins than the MHC genes (although the MHC and Ig genes are distantly related) and is not located in the MHC complex.  If this molecule is not produced, there are no HLA antigens and a cell may escape detection by cytotoxic T cells.

 

 


MHC II

The class II gene families are only known in therian mammals.  The majority of the genes in the class II families are of recent origin, being shared by Old World monkeys and apes but not by New World monkeys.  There may be ancient genes which predate the split of anthropoid primate lineages, such as DQB, but this gene seems to be nonfunctional (Kreiner, 2001).

 

MHC
     Cells which are known as antigen presenting cells (APCs) process antigens after phagocytosis through their binding to MHC II proteins and being carried to the cell membrane.  These APCs present the antigen to T lymphocytes to initiate the cell mediated humoral response.  Monocytes (which will later mature into macrophages and are represented in the following images) are important APCs.
MONOCYTES MONOCYTE

--HLA-DR

--There are 2 subunits: HLA-DRA and HLA-DRB.

--HLA-DRA

HLA-DRB

--The polymorphism of this locus predates the split of human and chimp ancestors and gives evidence for multiregional evolution of human evolution.  About 135 alleles are known (of which over 90% evolved after the split between human and chimp ancestors); some alleles offer resistance to malaria (OMIM). Although the DR region of the MHC complex was established before the split with NW monkeys, many of the DRB genes have arisen since then (Satta, 1996).

 

 

 

HLA-DP

     Different alleles of HLA-DPB1 cause susceptibility to beryllium disease which can affect those who work in which tech ceramics production, electronics, and aerospace industries.

 

HLA-DQ

     Specific alleles are involved in diabetes mellitus, narcolepsy, pemphigus vulgaris, and resistance to Creutzfeldt-Jakob syndrome.

 

COMPARISONS BETWEEN HUMANS AND CHIMPANZEES

     Chimps possess orthologs of all human HLA genes (Anzai, 2003).  Not only do human and chimps have the same genes, they also have similar alleles, indicating that the origin of some of the human alleles predate the split between chimp and human ancestors (OMIM).

Some alleles of the HLA-A and HLA-B genes are shared between humans and chimps and thus arose before the split between their lineages. The HLA-Cw*0702 seems to have arisen before the separation of the higher ape lineages, producing alleles in humans, chimps, and gorillas (Matsui, 1999).

     In general, it seems that chimps and humans share 98.77% of their nucleotides and more than 99%  of the amino acid sequences of their proteins (Anzai, 2003).  In the MHC complex, the sequence similarity of MHC genes is slightly less than that of non-MHC genes between chimps and humans (Anzai, 2003).  Most of the difference between human and chimp sequences in the MHC complex are due to origins and insertions rather than nucleotide substitutions.  Once origins and insertions are taken into account, sequence similarity drops into the mid 80-percentiles (Anzai, 2003).

    In humans, some MHC alleles decrease the risk of contracting HIV (such as HLA-A2, A28, and B18) while others increase the risk (such as A23) (OMIM).  The variation of chimpanzee MHC sequences is much lower than that of humans although mitochondrial DNA and many nuclear genes of chimps are more variable.  Given this reduction of the MHC variability and the resistance of chimps to HIV infection, it is possible that an HIV-like virus outbreak caused a reduction of chimp MHC diversity (de Groot, 2002).

     All populations of native Americans have small HLA polymorphisms, indicating that their ancestral populations were small.  Most HLA-B variations in native American populations evolved after their ancestors colonized the Americas (OMIM). 

 

MHC III

       In the MHC III region, nonhomologous molecules which share similar function are clustered together.  This is a rare phenomenon in eukaryotes.  Perhaps this is a type of “eukayotic operon” in which genes which function together are regulated together (OMIM; Nonaka, 1997).  The MHC class III region includes 57-60 genes, all of which are known in mice.  The genes in the MHC class III region include Notch4, the PBX homeobox, the NG2 Ring Finger protein CREB-RP, CYP21B of the cytochrome 450 group, and the complement genes C4A, C4B, C2, and complement factor B (BF).  The genes RP, C4, CYP21, and TNX comprise a region which can be duplicated and in humans, the number of copies of this region can vary from one to three (or perhaps even four) in a haploid set (Yu, 2000).

     It seems that three subunits of the proteasome, 2 heat shock proteins, precursors of complement proteins C3, C4, and C5, and perhaps ABC cassette proteins were organized into a single chromosomal region which was duplicated in the early vertebrates (Kasahara, 1996).  Cells contain a multi-subunit proteasome which prepares peptides for presentation by the MHC proteins (Kasahara, 1996). 

 

ODOR

     Mice preferentially mate with individuals dissimilar MHC genes.  Mice can be trained to distinguish between urine samples whose donors differ only in MHC loci and untrained mice have been shown to discriminate between the odors of mice which differ only in the alleles of a classical MHC gene (dm2).  MHC genes are thus involved in odor (Penn, 1998). Thus, natural selection would have acted on MHC molecules in both their capacities to defend against pathogens and for their odor (Carroll, 2002).

     Male mice preferentially mate with females with different MHC proteins and females preferentially nest with females with similar MHC proteins (Beauchamp, 2000).  In mice, fetal MHC proteins produce odors that can be detected in maternal urine.  Male mice can distinguish between, and react to, the odor in maternal urine, showing a preference for females whose fetuses carried MHC proteins differing from those of the male (Beauchamp, 2000).  Females prefer urine of uninfected males (Ehman, 2001).  Untrained mice an distinguish between some but not all MHC alleles (Carroll, 2002).

     There is some evidence that MHC differences are a factor in determining the reaction to the sweat of other people.  Surveys have shown that odor is a more important determinant for human females than males (Herz, 2002). Homologs of MHC proteins have been identified in the brain where they perform non-traditional roles, such as facilitating vomeronasal receptors (Olson, 2006).

      There are other proteins that can identify a cell as “self”.  CD47 is involved in the increased calcium concentration in the cytoplasm of cells once they have bound to the extracellular matrix.  Macrophages require this protein to fuse in order to become osteoclasts.  It is critical as a marker of self for red blood cells.  Red blood cells lack MHC proteins and would be destroyed by macrophages at the spleen and natural killer cells if they did not express CD47.

 

The CD1 family is related to MHC proteins and can present lipid antigens to T cells. They are known to exist in birds as well as mammals (Miller, 2005).