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IMMUNOGLOBULINS

IMMUNOGLOBULIN/FIBRONECTIN SUPERFAMILY

    One of the first problems that animals had to solve was how to be multicellular.  In a multicellular organism, cells must interact with each other (as in the cells of sponges and hydra depicted below).

Sponge:

sponge

Hydra:

hydra

Once cells began to express the immunoglobulin domain on their cell surfaces, other cells expressing the same (or slightly different) domains could interact with them.  As vertebrate animals began to live longer (and put off reproduction until later in life), the issue of distinguishing between one’s own cells and foreign cells became ever more important and important families within the immunoglobulin superfamily (IgSF) evolved such as MHC  proteins, Antibodies, and T-Cell receptors.     

     The immunoglobulin superfamily was one of the first identified and is one of the largest in vertebrates.  The immunoglobulin domain consists of about 100 amino acids arranged in two antiparallel β sheets.  Hypervariability in the loops at one region of the domain allows antibodies to bind a great diversity of specific molecules.  Many immunoglobulin molecules possess multiple copies of the immunoglobulin domain.  Constant chains are shorter than variable chains (since they lack the C’ and C’’ strands).  CD7 and CD8 possess one IgSF domain while sialoadhesin possesses 17 (Barclay, 2003). 

     Immunoglobulins appeared and diversified early in animal evolution.  There is some evidence of fibronectin and immunoglobulin domains existing in bacteria (Aravind, 2003, Angata, 2002).  It seems that extensive gene duplication occurred before the origin of animals which gave rise to new domains and multidomain proteins (Muller, 2001a).  The immunoglobulin domain is the 34th most common domain in the worm genome, the 9th most common domain in the fly genome, and, with its presence more than 850 human genes, may be one of the most common domains in humans. Only 84 genes are known in tunicates and 46 in nematodes; the number has clearly increased with the evolution of vertebrate immune mechanisms. (Liu, 2001; Barclay, 2003). 

   A very early duplication of ancestral immunoglobulin/fibronectin molecules produced fibronectin and immunoglobulins.  The functional domains of each of these molecules became incorporated into a variety of multi-domain proteins which can have single or multiple fibronectin domains and single or multiple immunoglobulin domains.  There are many molecules (such as the CAMs, contactin, nephrin, myomesin, MERTK, PUNC, TIE2, ROBO1, CRLF1, contactin3) which contain both fibronectin and immunoglobulin domains (depicted in green below).

domains
     The following summary of the immunoglobulin/fibronectin gene superfamily will introduce fibronectin and a number of molecules which contain fibronectin domains, then a number of proteins which contain immunoglobulin domains (including those which possess both immunoglobulin and fibronectin domains).  The following chapters will address groups of immunoglobulins which are essential for immunity including the MHC proteins, the antibodies, and the T-cell receptors.
areolar

FIBRONECTIN

     In multicellular animals (as in mammalian areolar tissue pictured above), cells must interact with neighboring cells and with the matrix that surrounds them (with components such as collagen and proteoglycans).  Fibronectins (part of the fibronectin/immunoglobulin superfamily) are important in a cell’s binding to collagen and other parts of the matrix.  This binding affects the cell: it can determine cell shape and is important for cell migration.  White blood cells rely on fibronectins in migrating to a wound site and neural crest cells (cells around the neural tube in vertebrate embryos which will produce many of the characteristic structures of the vertebrate head) rely on fibronectins in their migrations during embryonic cevelopment. 

     Fibronectin chains consist of two linked chains (a dimer, linked by disulfide bonds).  In each chain, there are repetitions of three different short amino acid sequences.  For example, there can be 12 copies of the Type I repeat, 2 copies of the Type II repeat, and 15 copies of the Type III repeat (Darnell, p. 923).

     Fibronectin is expressed on most cells and enables them to bind collagen.  Fibronectin also represents 1% of serum proteins.  Different fibronectin domains can bind different molecules such as collagen, heparin, and hyaluronic acid.  It is the major glycoprotein on the surface of many fibroblasts and, after an average of 25 hours, it is shed into the surrounding cell fluid.  It is involved in the endocytosis of debris.  It is also involved  in contact inhibition and is greatly reduced in many tumor cells.

     Fibronectin is known in sponges and is thought to have evolved just prior to the evolution of animals.  Although there is one case of fibronectin known in bacteria, it probably originated through horizontal transfer (Muller, 2001; Muller, 2001b). 

 

 Tenascin

     Tenascin seems to regulate collagen deposition by dermal fibroblasts (as in the image of a mammalian tendon below; the pink fibers are collagen and the small dots are fibroblasts which make the collagen).  It is the first gene other than collagen genes or collagen-modifying genes to be implicated in Ehlers-Danlos syndrome.  Tenascin C is expressed in adult astrocytes.  Its function is unknown since knockout mice seem to be normal.

tendon

Tenascin Receptor is expressed in the CNS.

 

Colony Stimulating factor , Immunoglobulin-like 3, cytokine receptor

--CSF3R is a transmembrane receptor that inhibits cell proliferation.

Myosin binding protein associates with myosin on striated muscle. 

 

Interleukin 13 receptor 1 alpha

 

Cytokine receptor-like factor 2 is expressed on leukocytes.

 

Macrophage mannose receptor recognizes carbohydrates.

 

MMPs Matrix metalloproteinases degrade the extracellular matrix.

     MMp2 cleaves type IV collagen of basement membranes and, as a result, is involved in the metastasis of tumor cells.  (In the image of the mammalian esophagus below, the basement membrane which separates the epithelial lining of the esophagus from the deeper connective tissue is evident).  It functions normally in inflammation and in breaking down the endometrium in menstruation.  Mutations in this gene cause the osteolysis observed in the “vanishing bone” syndromes. 

esophagus

     MMP9 cause neutrophils to degrade the matrix after being exposed to interleukin8.  Variations in this gene are linked to the smoking-induced emphysema and the severity of atherosclerosis.  Mice with mutations in this gene also have skeletal and autoimmune abnormalities.

 

Ephrin Receptors and Ephrin-related receptors are the largest subfamily of receptor protein tyrosine kinases.  They are important in development, especially in the nervous system.

EPHB3 is expressed during embryonic development.  Mice with mutations in this gene have craniofacial abnormalities, limb abnormalities, and cleft palate.

EPHB4 is expressed in endothelia, especially that of veins and is involved in the remodelling of capillary beds.

 

Sortolin-related receptor

    

Phospholipase A2 receptor 1 is involved in inflammation.  This protein is also contained in some snake venoms.

 

Lymphocyte antigen 75 is expressed in a number of tissues.  Dendritic cells use it in antigen presentation.

 

PTPR

     Protein-tyrosine phoshatase, receptor type F is a gene with 33 exons, 3 immunoglobulin like (exons 3-7) and 8 fibronectin (exons 8-17).  Exons 18 to 22 encode the transmembrane domains and 23 to 33 compose two tyrosine phosphotase domains.  

PTPRF: Mutations in this gene cause abnormal development of mammary glands.

PTPRH has been overexpressed in some colorectal cancers.

PTPRK is expressed in cell junctions and is involved in cell adhesion and contact. 

 

PTPRMCl is expressed in glomerular mesangial cells.

PTPRO is expressed in the lungs and placenta (such as the cells of the human lung pictured below).

lung

FNL2

 

FLRT 1-3


MOLECULES WITH IMMUNOGLOBULIN DOMAINS

(some of the following molecules also possess fibronectin domains)

  An immunoglobulin-like domain is present in the extracellular part of the receptor tyrosine kinase in some sponges (Schacke, 1994b). Two Ig-like molecules are known from fruit flies, another from squid, and from sponges (the C2 set of Ig domains) (Schacke, 1994a; Muller, 2001b).  Sponge cells are depicted below.

sponge

CELL ADHESION MOLECULES (CAM)

--These members of the Immunoglobulin superfamily are found in both vertebrates and invertebrates.  The CAM proteins have multiple Ig and fibronectin domains and a number of CAM molecules have a series of tandem immunoglobulin domains.  Most cells express multiple CAMs which can interact with CAM molecules of neighboring cells.  The immunoglobulin domains of CAM molecules are similar to those of cadherin and titin.

 

NCAM—neural CAM

-- N-CAM molecules possess 5 Ig-like domains and 2 fibronectin domains.  All 5 Ig-like domains are required for N-CAM molecules to bind other N-CAM molecules in cell adhesion.  Insects and Aplysia possess immunoglobulin molecules homologous to NCAM (Ranheim, 1996).

 

LCAM—liver CAM

--LCAM is expressed in both the embryonic and adult liver.  The following image is of the liver of an embryonic pig.

liver

MCAM—melanoma CAM

--The metastasis of melanoma cells involve changes in cell adhesion.

EPCAM—epithelial CAM

--Mutations can be involved in colorectal cancer.

OBCAM—opiod binding CAM

--OBCAM binds opiods and interacts with opiod receptors.

LICAM

--LICAM is involved in interactions between neural cells (human neuronal cells are pictured below).  Some mutations cause X-linked hydrocephalus.

neuron

--NRCAM—neuronal CAM

--NRCAM is involved in development and interacts with other proteins of the immunoglobulin superfamily.

--PECAM

PECAM is expressed in plateletes, monocytes, neutrophils, and some T cells and can interact with collagen (turtle blood cells are depicted below).  It is also expressed in endothelial cell junctions which may contain about a million molecules of PECAM.

blood

ALCAM—activated leukocyte CAM

ALCAM is expressed in the thymus.

ICAM—intercellular CAM

--This group of 3 genes allow T and B cells to interact with other cells.  ICAM1 is expressed in blood vessels and is an inflammatory signal to immune cells.

MADCAM—mucosal vascular addressin CAM

MADCAM is involved in the migration of leukocytes to mucous membranes.

 

CEACAM

     This family of genes is expressed in epithelial and myeloid cells.  Loss of their expression often leads to colorectal cancer.  There are 8 genes in tandem near the family of pregancy derived glycoproteins, to which they are related (Carl, 2001).  There are 29 members (genes and pseudogenes) of the carcinogenoembryonic (CEA) gene family in humans in a 1.5 Mb section of chromosome 19..  Much of this expansion has occurred in primates after separation from other placental orders (Zhou, 2001).

 

Pregnancy Specific Glycoproteins PSG

     There are about a dozen genes arranged in tandem which form a family of pregnancy specific glycoproteins in a stretch of about 1.1 megabases.  They are made in the placenta and low levels of these proteins are correlated with problems in pregnancy.  Inside the family of PSGs, there is a family of CEACAM pseudogenes.

 

IgJ polypeptide is a linker protein.  Five IgM antibodies can be joined to it to form the secreted IgM pentamer.  Two IgA antibodies can be joined to it to form the secreted IgA dimer.

 

FGFR Family

     The family of Fibroblast Growth Factor Receptors (3 separate genes) consist of proteins with 3 extracellular immunoglobulin domains, 1 membrane spanning domain, and a cytoplasmic tyrosine kinase domain.  Mutations in these receptors can cause a variety of human disorders including achondroplasia and hypochondroplasia.

 

CD79b

--This protein is needed for the assembly, transport, and function of B cell receptors.  Some mutations here have been linked to leukemias.

 

IGSF1 is conserved in mammals and is homologous to receptors found on natural killer cells.  It is expressed in muscle, the heart, brain, and testis.

IGSF4 (BL2) functions in the suppression of lung cancer.

IGSF6 is involved in the antigen presentation of dendritic cells.

skeletal muscle

--Titin

     Titin (a component of human skeletal muscle pictured above) is the largest known protein with a size of 3,000 kD (its mRNA is 100 kb).  It contains 244 copies of immunoglobulin and fibronectin domains.  Mutations in the gene can cause cardiomyopathy.

Titin, twitchin, and projectin form a family of large kinases which possess a series of immunoglobulin and fibronectin domains.  The immunoglobulin domains are intermediate between constant and variable Ig domains.  Titin isoforms may possess 165 immunoglobulin and 132 fibronectin domains.  Twitchin is known in C. elegans (Kenny, 1999).  Flies also express titin in their sarcomeres in addition to in association with chromosomes during mitosis.  Human and flies possess homologous members of the titin/myosin light chain kinase family.  Both the human sm/nmMLCK and fly MLCK-like genes possess internal promoters and are second in size only to the titin proteins (Champagne, 2000). 

 

Myotilin is found in skeletal and cardiac muscle.  Mutations can cause limb girdle muscular dystrophy type 1A.

 

Myomesin 1 associates with titin in skeletal muscle.

 

Eva functions in cell adhesion and is expressed in the liver, GI tract, skin, testis, fetal thymus, and embryonic primitive streak stage.

 

Syndecan 1is a receptor which interacts with the extracellular matrix and is associated with Wnt’s ability to cause tumors.

 

Contactin 1 and 3 are involved in axon growth.

embryo

--Protein 239 is expressed during fetal development.

 

Group Specific Component binds vitamin D.  Polymorphisms of the protein can be related to geographic variation in sunlight intensity.

 

Poly-Immunoglobulin Receptor

     This protein has 5 domains homologous to V regions and is expressed in glandular epithelia (such as the liver and the breast).

 

Immunoglobulin Superfamily with Leucine-Rich Repeat ISLR

     ISLR possesses both immunoglobulin and leucine-rich repeat domains.  It is expressed in the retina, heart, skeletal muscle, prostate gland, ovary, small intestine, thyroid, adrenal cortex, testis, and stomach.

 

IRTA1 is expressed in the tonsils.

IRTA2 can exist as different isoforms and is expressed in the lymph node, spleen, bone marrow, and small intestine (the frog small intestine is pictured below).

frog intestine

SIGIRR is a protein with both immunoglobulin and interleukin IR domains.

 

 TIE Receptors have immunoglobulin, EGF, and tyrosine kinase domains.

 

Basigin

     Basigin is the protein which composes the OK blood group. It is widely expressed and mutations in mice cause infertility and abnormalities of the CNS (in memory and sensation).  It has sequence similarities to both MHC II molecules and immuglobulin V domains.  It is possible that primordial members of the immunoglobulin family were similar to basigin (OMIM, Miyauchi, 1990; Miyauchi, 1991).

 

AAMP is expressed on endothelial cells where it binds heparin.

 

Glycoprotein 6 is expressed on platelets, allowing them to bind collagen.

 

Homolog of Drosophila Roundabout is involved in axonal growth.  This protein has homologs in both Drosophila and C. elegans.

 

MOG is expressed on myelin sheaths (pictured below).

axon

G6B is expressed both on the cell membrane and on the membrane of the ER.

 

PTPRC is expressed in all marrow cells involved in hematopoeisis except those involved in the production of red blood cells.  It has both immunoglobulin and tyrosine kinase domains.  Mutations cause SCID and a susceptibility to multiple sclerosis.

 

Uteroglobin is a secreted protein of the endometrium whose release is prompted by progesterone.  Mutations in mice cause renal disease.

 

M6P2 is expressed in epithelia.

 

TAX1 functions in axon growth.

 

Punc is involved in axon growth and has both immunoglobulin and fibronectin domains.

 

UNC5 is involved in neuron migration and possesses both immunoglobulin and thrombospondin domains.  Mutations in mice cause cerebellar abnormalities.  Homologs are known in C. elegans.

 

Poliovirus Receptors are immunoglobulins which are expressed in the nervous system.  Primates, which express them, can contract polio while mice, which do not express them, cannot contract polio.

 

Poliovirus Receptor Related Protein 1 is expressed in epithelia and the nervous system and is involved in the entry of herpes viruses 1 and 2.

 

HVEB is involved in the entry of herpes virus and is related to the poliovirus receptor.

 

Coxsackie and adenovirus receptors are immunoglobulins.

 

Lutheran Blood Group

     The proteins which compose the Lutheran blood group have 5 disulfide-bonded immunoglobulin domains and serve as receptors for laminin.

 

Landsteiner-Weiner blood group molecules are immunoglobulins.

 

Nephrin is involved in cell adhesion in the glomeruli of the kidneys.  Mutations cause abnormalities in the kidneys.

Butyrophilin (BTN)  surrounds milk fat droplets in mammary cells secreting milk.

 

BTN-like 3 is expressed in the GI tract, testes, and leukocytes.

 

CTX, Xenopus Homolog-like is expressed in the stomach, colon, prostate, trachea, and thyroid.

 

IMMUNOGLOBULINS LOCATED ON LEUKOCYTES

About 1/3 of the receptors on the surface of white blood cells possess at least one immunoglobulin domain (Chretien, 1998)

Thy-1 is a simple immunoglobulin with only one Ig domain which is found on T cells, fibroblasts, and some brain cells.  It functions alone, without forming dimers.

 

Paired Immunoglobulin-Like Receptor a

--on monocytes, granulocytes, and dendritic cells

 

Membrane-bound IgMa

     This transmembrane immunoglobulin is associated with IgM on B cells.

 

Fc Fragment of IgG

--FCGR1A, FCGR1B, and FCGR1C are expressed on macrophages and monocytes.

--FCGR2A is expressed on monocytes, macrophages, neutrophils, natural killer cells, T cells and B lymphocytes (a human lymphocyte is pictured below); mutations are involved in lupus.

lymphocyte

--FCGR2B is expressed in macrophages, neutrophils, mast cells, and B cells; mutations are associated with autoimmune diseases.

--FCGR3A is expressed on neutrophils (a human neutrophil is pictured below), natural killer cells, and monocytes; mutations are associated with autoimmune diseases and susceptibility to viral infections.

neutrophil

--FCGRT is homologous to MHC molecules.  It is expressed in the intestinal epithelia of newborn mice where it functions to transport the IgG molecules from maternal milk.

 

Fc Fragment of IgA is expressed on neutrophils, monocytes, macrophages, and eosinophils where it is used in the phagocytosis of antigens which have bound IgA.

 

Fc Fragment of IgE

     Two genes (FCER1A and FCER1G) encode surface proteins of mast cells.

 

TIM3

     This receptor is expressed on Th1 T helper cells but not Th2 T helper cells and is involved in T cell interactions with macrophages.

 

Human lymph node pictured below with leukocytes expressing many of the proteins described here.

lymphocytes

CD2 is expressed on natural killer cells and T cells and interacts with LFA3 in the cytolytic response.

 

CD7 is expressed on thymocytes and mature T cells.

CD8A and CD8B are located on chromosome 2p12, closely linked to the kappa locus.  One pseudogene of CD8B is shared by humans, chimps, and gorillas (it is located on 2q12, on the opposite side of the centromere on chromosome 2).

 

CD19 is involved in signal transduction after B cells have bound antigens.

 

CD28 is expressed on T cells and dendritic cells and is involved in T cell proliferation.  Alternate splicing can produce different isoforms.

 

CD37 is expressed on leukocytes.

 

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.

 

CD48 is recognized by natural killer cells; it is involved in infections of Epstein Barr virus.

 

CD74 differs in structure from other members of the immunoglobulin superfamily.  It associates with the MHC subunits when they form in the endoplasmic reticulum after which it dissociates and is transported to the cell membrane.

 

CD80 is involved in B-T cell interactions.

 

CD83 is expressed on leukocytes and dendritic cells.

 

CD-Like Receptor Activating Cytotoxic Cells activates natural killer cells.

 

LY9 is involved in the interaction between T cells and accessory cells.

 

LY94 and LY95 activate natural killer cells.

 

Natural Killer Receptor 2B4 is expressed on natural killer cells.

 

NTBA is expressed on natural killer cells, T cells, and B cells.

 

LFA3 is involved in the cytolytic response and is expressed on T helper cells and Antigen Processing Cells.

 

MOX2 is expressed in tonsils and on splenic dendritic cells where it inhibits macrophages and inhibits autoimmune reactions.

 

Semaphorin 4D is a protein on B cells which contains both immunoglobulin and semaphorin domains.

 

SLAM is involved in T cell activation.

 

B71 and B72 are involved in T cell proliferation, cytokine production, and increased T cell survival.

 

other--TCRg2 sequence has a triplification of exon 2

 

A number of members of the immunoglobulin superfamily are upregulated during the progression o cancers and contribute to their malignancy.  The glycoprotein MUC18 is similar to a number of cell adhesion molecules and its expression is linked to the malignancy of melanoma (Sers, 1993).

 

Fruit flies use the immunoglobulin Dscam (the homolog of the Down syndrome cell adhesion molecule) in innate immunity. The ability to form over 32,000 splice variants enables significant immune specificity in this innate mechanism (Schulenburg, 2008).

The immunoglobulin binding factor family includes β microseminoprotein which is produced in the prostate, mucous membranes, and corpus luteum. The protein is produced in lancelets where it seems to function in the differentiation of ectoderm (Wang, 2005).