Anti-transglutaminase antibodies
Encyclopedia
Anti-transglutaminase antibodies (ATA) are autoantibodies against the transglutaminase
protein. Antibodies serve an important role in the immune system
by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign (for example, viruses) and also can be producd by the body (for example, cancer cells). Antibodies against the body's own products are called autoantibodies. Autoantibodies can sometimes errantly be directed against healthy portions of the organism making them, causing autoimmune disease
s.
High levels (titer
s) of ATA are found in almost all instances of coeliac disease
. Given the association of ATA with coeliac disease, and the prevalence of the latter, it is estimated that ~1% of the population have potentially pathogenic levels of ATA.
ATA can be classified according to 2 different schemes. Transglutaminase
isoform and the reactivity of immunoglobulin subclass (IgA
, IgG) toward transglutaminases.
(ATA or anti-tTG) are found in patients with several conditions, including coeliac disease
, juvenile diabetes, inflammatory bowel disease
, and various forms of arthritis
.
In Coeliac Disease, ATA are involved in the destruction of the villous extracellular matrix
and target the destruction of intestinal villous epithelial cells
by killer cells. Deposits of anti-tTG in the intestinal epithelium
predict coeliac disease.
is a layer of connective tissue that ensheaths a muscle fiber. The endomysium contains a form of transglutaminase called "tissue transglutaminase" or "tTG" for short, and antibodies that bind to this form of transglutaminase are called anti-endomysial antibodies or EMA for short, therefore targeting those cells for apoptosis
.
The antiendomysial antibody test is a histological assay for patient serum binding to esophageal
tissue from primate. EMA are present in celiac disease. They do not cause any direct symptoms to muscles, but detection of EMA is useful in the diagnosis of the disease.
) are the autoantibodies believed to cause dermatitis herpetiformis
.
are more frequently found in CD; however, ATA IgG are found in CD and at higher levels when affected individual had the IgA-less phenotype. The IgA-less phenotype is more common in CD than the normal population; however, one haplotype
, DQ2.5 is found in most CD, has genetic linkage
to the IgA-less gene
location.
. A recent study of children published in 2007 demonstrated that the level of ATA in correlates with the scalar Marsh score for the disease in the same patient. See the Coeliac wiki article for more information.
Inflammatory bowel disease. A study published in Nature in 2001 found high levels of anti-transglutaminase antibodies in Inflammatory Bowel Disease
- specifically in Crohn's Disease and Ulcerative rectocolitis.
Arthritis. Studies of patients with various forms of arthritis
showed highly increased frequencies of antibodies against guinea pig transglutaminase, human recombinant transglutaminase and peptidylarginine deiminase type 4 (PAD4). This suggests a potential for crossreactive antibodies between anti-tTG and anti-PAD4.
Juvenile diabetes and anti-tTG. Childhood (male) Type 1 diabetes
(T1D) increases the risk for CD and vice versa and the early signs of CD may precede T1D in many cases. A search for CD in juvenile diabates patients revealed that GF diet resulted in some improvements. A elevated number of diabetes patients have ATA along with increased numbers of gluten
-specific T-cells.
Asymptomatic ATA+. A recent screening of 7550 Briton's found 87 undetected ATA+.
In this study a 50% increase of ATA was associated with:
Similar studies
Symptomatic ATA+
Alcohol consumption. ATA correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis.
For most antigens, T-cells specific to those antigens develop, for autoimmunity
autoreactive T-cells are not suppressed or antigens escape the protective process. T-cells are stimulated by antigen, presented by MHC molecules (HLA in humans) and surface IgM on antigen reactive B-cells. These T-helper cells then stimulate B-cells to multiply and mature into plasma cell
s that make IgG to that protein.
In the case of Coeliac Disease, the current understanding is that tTG autoimmunity arises when T-cells are generated against wheat gliadin and similar gluten proteins of the trib
Triticeae
. The T-cells are defined by the ability to react to HLA-DQ8
and DQ2.5 restricted antigens and gliadin is one of the antigens. Gliadin is a favored dietary substrate for transglutaminase
because of many enzyme
reaction sites on gliadin. In disease, transglutaminase reacts with gliadin forming a linkage
. In forming this bond transglutaminase becomes linked to T-cell epitopes on gliadin. B-cells with surface IgM that react to transglutaminase can present it with bound gliadin peptides to T-cells which stimulate B-cell maturation and proliferation to plasma cells making IgA or IgM.
ATA changes the behavior of tTG. Some studies have revealed that antibodies
increase the activity of tTG, instead of inhibiting activity as is commonly encountered with function alterning antibodies. A recent study has shown that ATA also modify and increase replication in intestinal epithileal cells, by apparently interacting with cell-surface transglutaminase.
Links=
Transglutaminase
Transglutaminases are a family of enzymes that catalyze the formation of a covalent bond between a free amine group and the gamma-carboxamid group of protein- or peptide-bound glutamine. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation.Transglutaminases were...
protein. Antibodies serve an important role in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
by detecting cells and substances that the rest of the immune system then eliminates. These cells and substance can be foreign (for example, viruses) and also can be producd by the body (for example, cancer cells). Antibodies against the body's own products are called autoantibodies. Autoantibodies can sometimes errantly be directed against healthy portions of the organism making them, causing autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s.
High levels (titer
Titer
A titer is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positive or negative. The titer corresponds to the highest dilution factor that still yields a positive...
s) of ATA are found in almost all instances of coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
. Given the association of ATA with coeliac disease, and the prevalence of the latter, it is estimated that ~1% of the population have potentially pathogenic levels of ATA.
ATA can be classified according to 2 different schemes. Transglutaminase
Transglutaminase
Transglutaminases are a family of enzymes that catalyze the formation of a covalent bond between a free amine group and the gamma-carboxamid group of protein- or peptide-bound glutamine. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation.Transglutaminases were...
isoform and the reactivity of immunoglobulin subclass (IgA
IGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
, IgG) toward transglutaminases.
Transglutaminase isoform reactivity
Anti-tissue transglutaminase
Antibodies to tissue transglutaminaseTissue transglutaminase
Tissue transglutaminase is an enzyme of the transglutaminase family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis...
(ATA or anti-tTG) are found in patients with several conditions, including coeliac disease
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
, juvenile diabetes, inflammatory bowel disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
, and various forms of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
.
In Coeliac Disease, ATA are involved in the destruction of the villous extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
and target the destruction of intestinal villous epithelial cells
by killer cells. Deposits of anti-tTG in the intestinal epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
predict coeliac disease.
Anti-endomysial reactivity
The endomysiumEndomysium
The endomysium, meaning within the muscle, is a layer of connective tissue that ensheaths a muscle fiber and is composed mostly from reticular fibers. It also contains capillaries, nerves, and lymphatics...
is a layer of connective tissue that ensheaths a muscle fiber. The endomysium contains a form of transglutaminase called "tissue transglutaminase" or "tTG" for short, and antibodies that bind to this form of transglutaminase are called anti-endomysial antibodies or EMA for short, therefore targeting those cells for apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
The antiendomysial antibody test is a histological assay for patient serum binding to esophageal
Esophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...
tissue from primate. EMA are present in celiac disease. They do not cause any direct symptoms to muscles, but detection of EMA is useful in the diagnosis of the disease.
Anti-epidermal transglutaminase
Antibodies to epidermal transglutaminase (eGT, also keratinocyte transglutaminaseKeratinocyte transglutaminase
Protein-glutamine gamma-glutamyltransferase K is an enzyme that in humans is encoded by the TGM1 gene.Keratinocyte transglutaminase is a transglutaminase enzyme.-Pathology:...
) are the autoantibodies believed to cause dermatitis herpetiformis
Dermatitis herpetiformis
Dermatitis herpetiformis , or Duhring's disease,Freedberg, et al. . Fitzpatrick's Dermatology in General Medicine. . McGraw-Hill. ISBN 0-07-138076-0. is a chronic blistering skin condition, characterised by blisters filled with a watery fluid...
.
Immunoglobin subclass
ATA IgAIGA
Iga or IGA may stand for:-Given name:* a female given name of Polish origin. The name originates from the female given name Jadwiga and stands for gia,or gina in the USA....
are more frequently found in CD; however, ATA IgG are found in CD and at higher levels when affected individual had the IgA-less phenotype. The IgA-less phenotype is more common in CD than the normal population; however, one haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
, DQ2.5 is found in most CD, has genetic linkage
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
to the IgA-less gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
location.
Associated Conditions
Coeliac Disease. Most attention to anti-transglutaminase antibodies is given with respect to Coeliac DiseaseCoeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...
. A recent study of children published in 2007 demonstrated that the level of ATA in correlates with the scalar Marsh score for the disease in the same patient. See the Coeliac wiki article for more information.
Inflammatory bowel disease. A study published in Nature in 2001 found high levels of anti-transglutaminase antibodies in Inflammatory Bowel Disease
Inflammatory bowel disease
In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...
- specifically in Crohn's Disease and Ulcerative rectocolitis.
Arthritis. Studies of patients with various forms of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
showed highly increased frequencies of antibodies against guinea pig transglutaminase, human recombinant transglutaminase and peptidylarginine deiminase type 4 (PAD4). This suggests a potential for crossreactive antibodies between anti-tTG and anti-PAD4.
Juvenile diabetes and anti-tTG. Childhood (male) Type 1 diabetes
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
(T1D) increases the risk for CD and vice versa and the early signs of CD may precede T1D in many cases. A search for CD in juvenile diabates patients revealed that GF diet resulted in some improvements. A elevated number of diabetes patients have ATA along with increased numbers of gluten
Triticeae glutens
Triticeae glutens are seed storage proteins found in mature seeds of grass tribe Triticeae. Seed glutens of non-Triticeae plants have varieties of similar properties, but none singly can perform on a par with those of the Triticeae taxa, particularly the triticum species...
-specific T-cells.
Asymptomatic ATA+. A recent screening of 7550 Briton's found 87 undetected ATA+.
In this study a 50% increase of ATA was associated with:
- lower bone mineral density of the hip.
- lower hemoglobinHemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
levels - decreased weight.
- lower cholesterolCholesterolCholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
- higher blood glucose
Similar studies
- increased mortality, particularly to cancer
Symptomatic ATA+
- greater impairment of neurophysiologyNeurophysiologyNeurophysiology is a part of physiology. Neurophysiology is the study of nervous system function...
(peripheral neuropathies and motor neuron disease. - increased inflammatory bowel symptoms(not celiac or EMA).
Alcohol consumption. ATA correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis.
Mechanism of Autoimmunity
The antibodies to tissue transglutaminase follow a complex pathway of generation.For most antigens, T-cells specific to those antigens develop, for autoimmunity
autoreactive T-cells are not suppressed or antigens escape the protective process. T-cells are stimulated by antigen, presented by MHC molecules (HLA in humans) and surface IgM on antigen reactive B-cells. These T-helper cells then stimulate B-cells to multiply and mature into plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s that make IgG to that protein.
In the case of Coeliac Disease, the current understanding is that tTG autoimmunity arises when T-cells are generated against wheat gliadin and similar gluten proteins of the trib
Tribe (biology)
In biology, a tribe is a taxonomic rank between family and genus. It is sometimes subdivided into subtribes.Some examples include the tribes: Canini, Acalypheae, Hominini, Bombini, and Antidesmeae.-See also:* Biological classification* Rank...
Triticeae
Triticeae
Triticeae is a tribe within the Pooideae subfamily of grasses that includes genera with many domesticated species. Major crop genera are found in this tribe including wheat , barley, and rye; crops in other genera include some for human consumption and others used for animal feed or rangeland...
. The T-cells are defined by the ability to react to HLA-DQ8
HLA-DQ8
HLA-DQ8 is a human leukocyte antigen serotype within the HLA-DQ serotype group. DQ8 is a split antigen of the DQ3 broad antigen. DQ8 is determined by the antibody recognition of β8 and this generally detects the gene product of DQB1*0302....
and DQ2.5 restricted antigens and gliadin is one of the antigens. Gliadin is a favored dietary substrate for transglutaminase
Transglutaminase
Transglutaminases are a family of enzymes that catalyze the formation of a covalent bond between a free amine group and the gamma-carboxamid group of protein- or peptide-bound glutamine. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation.Transglutaminases were...
because of many enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
reaction sites on gliadin. In disease, transglutaminase reacts with gliadin forming a linkage
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
. In forming this bond transglutaminase becomes linked to T-cell epitopes on gliadin. B-cells with surface IgM that react to transglutaminase can present it with bound gliadin peptides to T-cells which stimulate B-cell maturation and proliferation to plasma cells making IgA or IgM.
ATA changes the behavior of tTG. Some studies have revealed that antibodies
increase the activity of tTG, instead of inhibiting activity as is commonly encountered with function alterning antibodies. A recent study has shown that ATA also modify and increase replication in intestinal epithileal cells, by apparently interacting with cell-surface transglutaminase.
Links=