Type 1 diabetes (T1DM) is an autoimmune disease caused by the destruction of beta cells first, leading to the destruction of related pancreatic islet function. In patients with this disease, generally their humoral immunity and cellular immunity cannot work normally. Humoral immunity is manifested by the presence of autoantibodies in the patient’s body, mainly including anti-insulin antibodies, anti-tyrosine phosphatase antibodies, and anti-islet cells, anti-glutamic acid decarboxylase antibodies, these abnormal antibodies will damage the insulin-secreting B cells of the human pancreatic islets, making them unable to secrete insulin normally. This article provides a multi-faceted review of these autoantibodies.

Causes of Type 1 Diabetes

Type 1 diabetes may be caused by genetic factors. According to current research results, it can be judged that genetic defects are the basis for causing this disease. This genetic cause is mainly manifested as an abnormality of the LHA antigen on the sixth pair of human chromosomes. What is very serious is that this genetic characteristic is familial. In other words, if parents have this disease, their offspring will have a much higher probability of developing diabetes than the offspring of normal people. Secondly, many experts also believe that viral infections can also cause type 1 diabetes. Because, at the beginning of suffering from this disease, there is often a history of viral infection, and it mainly appears after viral infection. Viruses such as rubella and the common mumps virus may cause type 1 diabetes.

Clinical Features of Type 1 Diabetes

The main characteristic is that this disease is prone to occur in adolescence and childhood. Another major concurrent stage is menopause. Therefore, people of these ages should pay more attention to self-care. Its second notable feature is that its onset is sudden and rapid, with the general characteristics of diabetes, namely “three more and one less”: polyphagia, polydipsia, polyuria, rapid body weight loss, thirst, and a very obvious rate of weight loss. The third well-known characteristic is that it is treated with insulin, so this is why it is called insulin-dependent diabetes.

Type 1 Diabetes Autoantibodies

Anti-Insulin Antibodies

The anti-insulin molecule is composed of 51 amino acids, with two disulfide chains connecting the A and B chains. Human insulin is different from animal insulin. For example, the main difference from bovine insulin is the A8 and A10 residues and the B30 residue, while the main difference from pig insulin is only the B30 residue. The antigens recognized by anti-insulin antibodies are B1, B2, and B3 residues of the insulin B chain and A8 to A13 residues of the A chain. In the human body, the immune system may interact with multiple forms of insulin, but only the most immunogenic molecule is likely to be preproinsulin or insulinogen.

There is a correlation between human leukocyte islet antigen, Kulmala, and anti-insulin antibodies. Many studies have shown that in children with T1DM, anti-insulin antibodies are associated with the DR4 and DQB1*0302 loci. The probability of children being positive for anti-insulin antibodies before the age of five is very high, reaching as much as 50%. This probability is generally inversely proportional to age. The probability of children with DQA1*0301 and DQB1*0302 being positive for anti-insulin antibodies is likely to reach 90%, and the probability of being positive for ICA is as high as 92%. If a relative with positive T1DM on ICA is also positive for anti-insulin antibodies, T1DM is likely to develop. The rate at which T1DM develops is closely related to anti-insulin antibodies. Patients with high anti-insulin antibody titers are often susceptible to the disease. Relevant experts conducted studies on 60 child patients in different groups based on the time difference between anti-insulin antibodies becoming positive. Anti-insulin antibodies have a high affinity for insulin. This high-affinity immune response speed accelerates the autoimmune cascade. This is the mechanism of T1DM. Many studies have shown that anti-insulin antibodies are significant immune markers in children with T1DM. Most children who are positive for anti-insulin antibodies have a variety of islet autoantibodies in their blood, which are closely related to T1DM.

Anti-Islet Cell Antibodies

In 1974, this anti-islet cell antibody was first discovered in the serum of patients with insulin-dependent diabetes. Anti-islet cell antibodies are actually a group of antibodies that mainly target multiple antigens in islet cells. The target antigen of anti-islet cell antibodies has not been specifically and clearly elucidated so far. Its target antigen is not only β-cells, but its distribution mainly has four forms, namely: (1) pancreatic islet cell-specific; (2) β-cell specific, such as the well-known insulin, which belongs to this category; (3) nerve Endocrine specific, such as tyrosine phosphosinase, brain tumor lipids and gangliosides; (4) HSP62. Judging from the current research status, the target antigens of anti-islet cell antibodies mainly include IA2 and GAD. However, first-degree relatives of T1DM patients who are positive for anti-islet cell antibodies and negative for GADA and IA2A may not have a high probability of developing diabetes.

In some patients, anti-islet cell antibodies bind only to beta cells, but in most cases they bind to four types of cells, namely alpha, beta, delta and PP cells. For the value of judging T1DM, anti-insulin cell antibodies binding to 4 types of cells will have a higher predictive value than binding only to β cells. The probability of positive anti-islet cell antibodies among new patients with T1DM is 60% to 90%, but the probability of positive anti-islet cell antibodies in the normal population is only 0.5%. If the titer is greater than 20~40JDF, the incidence rate is extremely high. Moreover, patients with unstable and fluctuating anti-islet cell antibody levels have a lower prevalence than those with persistent high or low levels. This persistently high titer is often positively correlated with β-cell damage and negatively correlated with C-peptide levels. The prevalence of patients with anti-islet cell antibodies coexisting with other islet cell autoantibodies is 3 to 5 times higher than that of patients with only anti-islet cell antibodies. In most cases, the onset of anti-islet cell antibodies in patients with T1DM does not exceed 2 years. Only 10% of patients with T1DM have persistently positive anti-islet cell antibodies for more than two years. Moreover, these patients generally have other related endocrine diseases. Antithyroid antibodies Antibodies like this type are often associated with a family history of autoimmune disease and are more common in women.

So far, the method for detecting anti-islet cell antibodies is indirect immunofluorescence (using monkey pancreas as the antigen sheet). In the 1880s, Sweden conducted an experiment to perform plasma exchange for new-onset T1DM patients. This plasma was used in the calibration test of anti-islet cell antibodies of the JDF organization, and the JDF unit of ICA was created. This unit is widely used.

Anti-Tyrosine Phosphosinase Antibody

The target antigen of this antibody is a CDNA library selected from the serum of T1DM patients to obtain a new β-cell antigen. Human anti-tyrosine phosphatase is a type I transmembrane glycoprotein with 979 amino acid residues, and the encoding gene is located on human chromosome 2q35. The structure of anti-tyrosine phosphatase contains protein PTP amino acids 696~979, so this antibody belongs to the receptor-type protein anti-tyrosine phosphatase superfamily. The content of anti-tyrosine phosphatase is relatively high in secretin-type endocrine cells and neurons, and can only be expressed in tumors (neuroendocrine). There are many factors that affect the positivity of anti-tyrosine phosphatase antibodies in patients with T1DM, such as the course of the disease and age. The production rate of this antibody in new patients with T1DM is relatively high, above 50%. In pediatric patients, the occurrence rate of this antibody is high and the disappearance rate is high. In adult patients, this antibody exists for a long time but the probability of illness is lower than in pediatric patients. T1DM patients over 15 years old who are IA2A positive show that the probability of such positivity becomes lower and lower with age. In first-degree relatives who are positive for anti-amino acid phosphatase antibodies, IA2A appears later than GADA. Once it appears, it indicates that T1DM is likely to occur. The detection method for this antibody includes radioimmunoprecipitation (marked 35S) , ELISA method, RLA method. Different methods have different characteristics. The sensitivity of ELISA method is not high, but RLA has high sensitivity in detecting anti-tyrosine phosphatase resistance.

Anti-Glutamic Acid Decarboxylase Antibody

GAD is a gamma-aminobutyric acid synthase, which has the function of inhibiting the secretion of related hormones. It can promote the synthesis of insulin and regulate the secretion of insulin. This enzyme is present in the human brain and pancreatic islets. Anti-glutamate decarboxylase is an autoantigen in type 1 diabetes. There are two isomers of anti-glutamic acid decarboxylase, GAD65 and GAD67. Although their coding genes are different, their homology and similarity are very high from the perspective of amino acid level. The main epitopes related to GAD65 and type 1 diabetes are the carboxyl terminus, the amino acid terminus, and the middle part of the molecule. Anti-glutamic acid decarboxylase antibodies mainly appear in SMS, T1DM, and APS2. In T1DM, the positive incidence rate of GADA is as high as 80%. Compared with other types of antibodies, GADA has a strong correlation with slow and impaired β-cell binding. It is characterized by an early appearance stage, a long sustainable time course, a high probability of being positive, and a relatively large age span, it is easy to predict the function of pancreatic β-cells, and the detection is easy to standardize.

Author's Bio: 

Creative Diagnostics is a leading manufacturer and supplier of antibodies, viral antigens, innovative diagnostic components, and critical assay reagents. We provide contract biologic R&D and manufacturing services to the diagnostic manufacturers along with GMP biologics manufacturing for the biopharmaceutical market. Our goal is to be a trusted source for all your assay development and manufacturing needs.