Autoimmune Disease Overactive Immune Response Attacks The Body Biology Essay


Autoimmune disease is the classification for when an overactive immune response attacks substances and tissues normally present within the body. The most common autoimmune diseases are rheumatoid arthritis (RA), Grave's disease, Hasimoto's thyroiditis, systemic lupus erythramatosus (SLE), type 1 diabetes (T1D), celiac disease and multiple sclerosis (MS). These diseases affect at least 5% of the population1. The genetic basis of these diseases is complex as multiple genes are typically involved. The genes responsible for allelic susceptibility are usually located at different loci and each individually generally playing a small role in the overall disease. The alleles of the major histocompatibility complex have been known to contribute to autoimmunity for over three decades1, however an increasing number of biochemical pathways have been associated with the development of autoimmunity as new technologies speed the process of identification of novel loci.

An interesting class of enzymes are protein tyrosine phosphatases (PTPs). PTPs catalyse the removal of phosphate groups from phosphorylated tyrosine residues on proteins. This relatively common post-translational modification can create novel recognition motifs with a range of functions, such as regulation of enzyme activity. PTPs, together with tyrosine kinases, are involved in the regulation of the phosphorylation state of many important signalling molecules, including members of the mitogen-activated protein kinase family which regulate various cellular activities including gene expression, mitosis, differentiation, proliferation and apoptosis2.

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A total of 107 genes in the human genome encode experimentally verified PTPs or probable PTPs, which contain a domain which is homologous to the catalytic domain of the verified PTPs3. Of these 107 genes, 81 products are predicted to be active protein phosphatases, 13 are dephosphorylate inositol phospholipids, 2 are dephosphorylate mRNA and 11 are catalytically inactive4. There are four evolutionarily distinct classes of PTPs, based on the primary structure of the catalytic domains; dual specificity phosphatases (DSPs), low molecular weight phosphatases, CDC25 phosphatases and pTyr -specific phosphatases. Class I PTPs are the largest group of PTPs with 99 members, consisting of 38 classical PTPs and 61 DSPs. The classical PTPs can be divided further into two catagories; receptor and non-receptor PTPs. Class II contains only one member, a low molecular weight PTP, and class III has three members of which all are CDC25 phosphatases4.

Most PTPs are involved in inhibiting T-cell receptor (TCR) signalling. Approximately 20 PTPs have been evidenced to regulate signalling events between the TCR and transactivation of the interleukin-2 gene5. Although most PTPs play an inhibitory role in TCR signalling, a few have a positive regulatory role. TCR signalling is an important part in immune cell signalling, and as a regulatory component PTPs may play a role in autoimmune disease.

Individual PTPs range in expression patters from cell to cell and tissue to tissue. Approximately 30% to 60% of cells in the human body express the entire complement of PTPs, however neuronal and hematopoietic cells express a relatively high number of PTPs compared to other cell types4. For example, T cells and B cells express a slightly different set of between 60 to 70 different types of PTPs5.

Some PTPs are restricted to individual cell types. Lymphoid tyrosine phosphatase (LYP), the product of the gene PTPN22, is expressed only in hematopoietic cells5. LYP is a member of the class I non-receptor type, and has been shown to be involved in the regulation of the function of the protooncogene CBL in the TCR signalling pathway, the regulation of the immune system and the development of autoimmunity and involved in preventing spontaneous T-cell activation through dephosphorylation and inactivation of TCR-associated C-src tyrosine kinase (CSK)6.

LYP is a ≈105 kD protein characterised by a ≈300 amino acid N-terminal tyrosine phosphatase domain and a ≈200 amino acid C-terminal domain, which includes four proline-rich Src homology 3 (SH3) domain binding sites termed P1 to P49. The catalytic domain and the C-terminal domain are separated by a ≈300-aa region called "the interdomain", a region with of currently unknown function. Several isoforms of LYP have been observed in resting T-cells but western blotting techniques reveal that the full-length LYP is the predominant isoform in these cells10. Within the cell, LYP is primarily localised in the cytoplasm however a mouse homolog of LYP (PEP) can be found in small amount within the cell nucleus. The localization of LYP and PEP in cells is poorly understood, however several binding partners have been identified. For example, the C-terminal of Src kinase (Csk) binds to the P1 region of LYP and PEP through a protein domain of approximately 60 amino acids capable of binding proline-rich motifs (SH3), resulting in the localization in the cytoplasm11. A single consensus protein kinase C (PKC) phosphorylation site on ser-35 is present and 11 proteins have been identified that interact with LYP; CD247, CDH2, ERBB2, GHR, LCK, NTRK1, PDGFRB, PDPK1, WAS, ZAP70 and GRB26.

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Perhaps the most established function of LYP is its potent negative regulation of TCR signalling. This is the result of LYP activity directed at removing the activating phosphate at of the positive regulatory tyrosine residues of lymphocyte-specific protein tyrosine kinase (Lck), Src family kinases, FynT and ZAP-707. This prevents Lck from interacting with the cytoplasmic tails of the CD4 and CD8 co-receptors on T-cells and thus prevents signalling from the TCR complex8. Hence, LYP inhibits TCR signalling by acting immediately downstream of the TCR.

Most of scientific endeavour into LYP focuses on T-cells, however LYP has been identified in other leukocyte lineages such as B-cells. In these cells, LYP forms a complex with CSK, which is also a negative regulator of TCR signalling. The complex is dependent on an interaction between the most N-terminal P1 motif of LYP and the SH3 domain of CSK7. The high stoichiometry of the complex in T-cells point may indicate an important physiological function. Research with PEP, the mouse homologue to LYP, suggests a synergistic inhibition of TCR signalling12. However, more research is required to clarify the function of the complex in TCR signalling.

Although the cellular mechanisms for disease development are not completely known, reduced TCR signalling molecular mechanism of disease can potentially lead to reduced negative selection in the thymus, reduced activity of Treg cells and altered activity of other hematopoietic cells4. This, in turn, may manifest as the autoimmune diseases associated with PTPN22; T1D, RA, SLE, etc.

Unfortunately, little is known about the role of LYP in the immune system in vitro. What little information we have determined has been through the use of a PTPN22 knockout mouse. The mouse ortholog of LYP has been identified and called PEP9. Both LYP and PEP share 89% identity between PTP domains, 61% identity with their noncatalytic portions and are expressed exclusively in hematopoietic cells in both species. The current level of knowledge regarding LYP is derived from studies of PEP, although evidence shows subtle biochemical differences in some assays4. Although our knowledge about LYP and PEP are generally derived from studies on T-cells, LYP and PEP are expressed in other leukocyte lineages.

Knockout mice deficient in PEP (PEP -/-) have been created. The mice appear to have normal resting T cell numbers and subpopulations but have enhanced memory T-cell responses13. Elevated and sustained TCR-induced phosphorylations of Lck, as well as augmented proliferation, are associated from restimulation of the T-cell in these mice. A redundancy in the PEST motif in PRP-/- mice may explain the lack of a noticeable phenotype in native T-cells4. Another interesting note is that, although the vast sum of knowledge about LYP and PEP is derived from studies on T-cells, the enzyme is produced in other leukocyte lineages. In PEP -/- mice, the B-cell population and IgG production are both elevated, but it remains to be determined if the effects on the B-cell population are intrinsic or secondary to the known associated T-cell defects13.

The phenotype outlined above supports the belief that in TCR signalling, PEP plays an important negative regulatory role. High expression of phosphatase in the PEP -/- mouse is in line with the prominent effector/memory T-cell phenotype.


Gene Structure (what is the approximate gene size overall, approximate mRNA size, and number of exons? Are there alternative transcripts and how do they differ structurally?)

The total size of the gene is 57,898 bases in length coding for a total of 807 amino acids to product a final protein with a molecular weight of 91,705 Da. There are 24 exons in the gene and 21 transcript variants encoding for 10 distinct proteins?WikiPTPN22.

Gene Mapping (on which human chromosome is the gene found and on which arm/band/sub-band?)

PTPN22 has been mapped to the short arm of chromosome 1 near the telomere (1p13.2) on the Crick (minus) strand. This region associated with rearrangements in solid and hematopoetic tumors?Cohen.


SPECIFIC Gene Function (briefly, what is the function of the protein encoded by the gene?)


The LYP protein forms an inhibitory heterodimeric complex with the Csk, an enzyme which is partly responsible for regulating the activation state of Lck.

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TYP has a catalytic role in the hydrolytic breakdown of the protein tyrosine phosphate into tyrosine and phosphate?Uniprot.

Clinical Aspects

Clinical Relevence (is the gene associated with a human disease or diseases, and if so, which ones?)

In human autoimmune diseases, research into any one particular gene generally yields few rewards, as numerous genes usually contribute to the complex autoimmune diseases with each gene individually having a small effect.

The first report of PTPN22 mutation contributing to an autoimmune disease was a missense functional polymorphism R620W contributes to type 1 diabetes (T1D)?Bottini. Further research into a study of 87 potential functional single nucleotide polymorphisms (SNPs) identified PTPN22 with rheumatoid arthtritis (RA)?Begovich and later systematic lupus erythramatosis?Kyogokyu, Graves' disease?Smyth, Addison's disease?Velaga, vitiligo?Canton, myasthenia gravis?Vandiedonck and systemic sclerosis?Gourh. This association is not a general autoimmune susceptibility gene, as no association to other immune diseases such as multiple sclerosis and Crohn's disease have been identified. In fact, research may indicate that the mutation has a protective effect in Crohn's disease?Barrett, and others such as Behcet's disease?Baranathan. The level of risk when the mutation is present appears to be variable amongst the diseases; however it is most substantial in T1D and RA?StephanieHard Copy. At the moment, the reason why PTPN22 associates with some but not other major autoimmune diseases is unclear but it appears that the polymorphism may have an association with diseases that have a strong autoantibody component?McGonagle.

The mechanism behind the disease appears to be due to a disrupted interaction site for the SH3 domain of Csk?Bottini. Patients homozygous for the PTPN R620W mutation have primary T-cells which produce less interleukin-2 following CD3 stimulation compared to those with wild-type genes?Vang2005. This may be due to an increased phosphatase activity of LYP.

Clinical Impact of Study of the Gene (has knowledge of the gene been harnessed to treat, prevent and/or diagnose the disease(s) with which it is associated? If so, elaborate on how this was achieved. If not, speculate on how this may be achieved in the future.)

Because the activity of the R620W mutation is about 50% higher than the nonmutated form ?Vang2005, research into drugs that may eliminate the effects of the mutation on TCR signalling have led to the development of small molecule inhibitors of LYP?Wu. Theoretically, a selective inhibitor of LYP could undo the negative effects on the TCR signalling process and as such may compose a drug mediated therapy of autoimmunity in carriers of the variant. Because of the implication of the R620W mutation in such a variety of autoimmune diseases, the drug would be of great value in treatment where multiple autoimmune diseases present clinically. Studies of the effect of the anti-LYP drug on knock out mouse models suggests that the drug will have limited side-effects?Xie.

A successful trial of monoclonal antibodies targeting CD3 for the treatment of T1D has been reported in literature?Chatenoud. This study also supports the idea, although it's not yet proven that autoimmunity is reversible, that positive modulation of the TCR helps to re-establish tolerance. Supporting this, it has been reported that a rare loss-of-function genetic variation LYP-R263Q may play a protective role in SLE.

To validate LYP as a drug target, further studies in animal models are needed. In particular, studies need to be performed to assess the risks of therapeutic inhibition of LYP in autoimmunity. It has been reported that inhibition may be counterproductive and lead to increased TCR signalling in effector T-cells in diseases or subsets of diseases with a strong component of TCR or BCR hyperactivity?Hermiston. Also, because of the complexity and plasticity of the immune system and the varied roles of the signalling molecules, the timing of such treatments and their strategy would have to be very carefully evaluated.

Also, how has research done on the gene had an impact on understanding the disease process/mechanism/pathogenesis? Overall, what appear to be the prospects for the future?)