Familial Mediterranean Fever is a recessively inherited systemic auto inflammatory disorder. The clinical symptoms include recurrent fever and serositis, and also cause pain in the muscles, abdomen, chest and joints.
This monogenic disorder is mainly prevalent among the people in Eastern Mediterranean region namely among in Jews, Armenians, Arabs and Turks. FMF is usually inherited as an autosomal recessive attribute but however there are certain rare cases were the FMF is found to be dominantly inherited transmitted. High consanguineous marriages and severity of certain mutations could be the molecular basis of dominant transmission. Twin studies in monozygotic twins have revealed that concordance rate of FMF is high as 100% and there is less contribution of environmental factors in the cause of disease.
FMF is found to be caused by the mutation in the MEFV gene (Mediterranean Fever). MEFV gene has 10 exons and encodes 781 amino acids with a protein product pyrin. So far 152 mutations and polymorphisms have been reported in MEFV gene and almost 70 % of the FMF cases arise due to five major mutations in exon 10 namely M694V, V726A, M680I, M694I and E148Q. However there are certain other mutations reported in 1, 2, 3, 5 and 9 exons. Most of these mutations are found to be single amino acid substitution mutation and some are duplication/deletion mutations.
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Pyrin is a multi domain protein and is expressed in monocytes, dendritic cells, synovial fibroblasts and granulocytes. Pyrin plays an important role in regulation of various processes such as apoptosis, inflammation, and also in regulation of cytokines. In polymorphonuclear cells, pyrin functions as a down regulator of inflammation. Studies on pyrin structure and function have given clarification and insights about the pathogenesis of FMF.
The N-terminal pyrin domain is found in many proteins and also the amino acid sequences are almost similar in these proteins, these proteins undergo protein-protein interactions and initiate the apoptosis and inflammasome. The other pyrin domain containing proteins which initiate inflammasome are adaptor protein and ASC. The ASC protein which also posses the N-terminal pyrin domain has a important role in Caspase-1 initiation and IL-1 β secretion. IL-1 β secretion depends upon the \N-terminal and C-terminal B30.2 pyrin domains. Several studies have found that C-terminal B30.2 domain is critical for FMF as many FMF mutations are found associated in this domain. The B30.2 domain consist of a C-terminal SPRY domain and N-terminal PRY Sub domain and it binds to procaspase -1 and also P10 and P20 catalytic subunits. It also acts as a mediator between the pyrin and major inflammasome components such as NLRP1, NLRP2, NLRP3 and Caspase-5.
As from earlier studies it is known that caspase 1 plays an important role in the proteolytic processing of inflammatory IL-1 cytokine. It was recently discovered that caspase-1 also cleaves the pyrin and activates NF-κB and a 451-residue C-terminal fragment. These results are consistent with the peripheral blood report from the FMF patients, were the pyrin is found to be in a cleaved form. Another controversy about the pyrin is that whether it is a nuclear factor as it is mostly localized in nucleus. It is also found that there is increase there is increase in T-cell mediated immunity in patients with FMF as there is a increase in Macrophage Inflammatory protein-1α (MIP-1 α) levels.
Thus the MEFV gene mutation is responsible for the clinical spectrum of FMV as it involves innate immune responses by modification of leukocyte apoptosis, regulation of IL-1β and activation of NF-κB. Several researchers are now focussed on finding suitable therapeutic target.
Myotonic dystrophy is the most prevalent neuro-muscular dystrophy inherited in an autosomal dominant pattern. The characteristic mutation in the Myotonic dystrophy involves nucleotide repeat or duplication in the gene, and is commonly mentioned as nucleotide repeat disorder. Unlike other muscular dystrophy, Myotonic dystrophy include a muti-system disorder as its clinical syndrome and it affects the skeletal muscles, eyes, uterine smooth muscles, heart, gastro-intestinal smooth muscle and central nervous system. Myotonic dystrophy is mainly classified into two types with mostly similar phenotypes namely myotonic dystrophy I (Steinert's Disease) and myotonic dystrophy II (Proximal Myotonic Myopathy)
Myotonic dystrophy Type I (Steinert's Disease):
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Myotonic dystrophy I is the most common form of muscular dystrophy which has a prevalence of about 1 in 8500 people. Myotonic dystrophy I involve wide clinical features and is basically classified into three categories namely mild, classical and congenital myotonic dystrophy.
Myotonic dystrophy I arise due to the increase in the triplet repeats in the DMPK gene. It is inherited in an autosomal dominant pattern and an anticipation phenomenon occurs whereby the offspring is severely affected when it has inherited the repeats in the DMPK allele from the mother. The anticipation phenomenon occurs when the CTG repeats in the DMPK gene exceeds more than 35 repeats become unstable and is inherited more to the offspring by increase in size during meiosis. This phenomenon not only increases the repeats but also enhances the disease severity and cause the disease in earlier age in successive generations.
Myotonic dystrophy I is caused due to the mutation in the chromosome 19 at the 3' UTR of the myotonia-dystrophica protein kinase gene with amplified untranslated CTG repeats and than the mutation is transcribed into RNA and is not translated into protein. The unaffected individuals usually has 35 CTG repeats while in the myotonic dystrophy patients the CTG repeats are more than 50. Three models have been proposed to understand the mechanism of CTG repeats in myotonic dystrophy namely haploinsufï¬ciency of DMPK, altered expression of neighbouring genes, and dominant-negative mRNA mutation.
In the first model it's been suggested that the clinical features of the disease are due to the reduced expression levels of the DMPK, although initially this hypothesis was consistent with the DMPK knock out mice studies as they possessed cardiac abnormalities, however DMPK reduced level did not show the full clinical features of the myotonic dystrophy. In the second model its been proposed that the expansion of the CTG repeats may have a effect in the expression levels of DMPK and neighbouring genes DMWD and SIX5, as the CTG expansion is a nucleosome binding site it was suggested that it could alter the chromatin structure and affect expression levels of neighbouring genes. Several studies have been carried out to verify this hypothesis by measuring the expression levels of DMPK, DMWD and SIX5 in diseased and healthy individuals. Although the expression levels of DMPK were similar in the diseased and healthy individuals, however the levels of DMWD and SIX5 were not consistent in diseased and healthy individuals. These results correlate with the hypothesis and shows involvement of other genes in the pathogenesis of myotonic dystrophy. In the third model it was proposed that the mutant RNA transcribed from the expanded CTG repeats is enough to cause the clinical features of the disease, the supporting evidence for this hypothesis was that the DMPK and surrounding genes in reduced levels failed to produce the disease clinical symptoms and also the accumulation of the CUG repeats transcribed from CTG repeats in the nuclei foci. This hypothesis correlated with the studies in the mouse model showing the RNA gain of function has a role in pathogenesis of the myotonic dystrophy. The possible reason could be the formation of hairpin like structures as a result of CUG repeats and the interruption of U-U mismatches with C-G base pairs in those structures.
Myotonic dystrophy Type II:
Myotonic dystrophy II is clinically similar and distinguishable from Myotonic dystrophy I. It was initially classified into three phenotypes namely proximal myotonic myopathy (PROMM), myotonic dystrophy 2 (DM2) and proximal myotonic dystrophy (PDM) and posses the clinical features such as myotonia, wasting, weakness, cataract, cerebral, endocrine and cardiac problems.
Myotonic dystrophy II is also inherited in a autosomal dominant pattern and also involves the anticipation phenomena were the successive generations are severely affected and the prevalence is similar to that of DM1.
Myotonic dystrophy II involves tetra-nucleotide repeat expansion (CCTG) in the ZnF9 gene located in the chromosome 3. Later it was found that this tetra-nucleotide repeat expansion (CCTG) is situated in the intron1 of the ZnF9 gene which encodes a ZnF9 protein product. These CCTG repeats varies from 75 to 11 000 CCTG repeats with a average of 5000 repeats in the patients. ZnF9 protein is a RNA-binding protein and is usually denoted as nucleic acid binding protein.
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Pathogenic mechanism leading to distinct phenotypes caused by DM2 is still unclear and is thought to have similar mechanism to that of DM1.It is also suggested that like DM1, the myotonic dystrophy II also occurs due to RNA gain function. Several studies are still going on to find the exact mechanism behind this dystrophy.
Type IV Hypersensitivity:
Body immune system produces an exaggerated immune response when it finds out a particular substance which can make some adverse effect inside the body, this type of immune responses are called as Type IV hypersensitivity. The Type IV hypersensitivity is also called as delayed type hypersensitivity as it takes 2-3 days to produce an immune response. The memory T cells are responsible for production of these immune responses upon there interaction with the antigens.
Crohns disease is an inflammatory bowel disorder of the gastro intestinal tract. The clinical features of the disease include abdominal pain, diarrhoea, weight loss and is usually linked with granulomas.
Epidemiological studies show that Crohns disease is prevalent in North America and Europe with an incidence rate of 10-200 cases per 10000 people. In Crohns disease genetic factors are found to have significant role in disease pathogenesis from the twin studies, with a incidence rate of 37.3 in monozygotic twins and 7% in dizygotic twins.
Crohns disease is a polygenic disorder and is related to chromosome 5 and 10. Crohns disease is caused due to the variations in ATG16L1, IRGM, NOD2 genes and also due to presence of bacteria in the gastro intestinal tract. It was also found that IL23R gene signalling pathways is also related with the immunopathogenesis of Crohns disease. The ATG16L1, IRGM, NOD2 and IL23R genes produces proteins which are responsible for the immune response, and variation in any of the above mentioned genes may lead to defect in the immune response, and affects the intestinal cells response to the bacteria present in the intestine. As a result of this Crohns disease characteristic such as chronic inflammation and digestive problems occurs.
Tuberculosis is largely caused infectious disease involving Type IV hypersensitivity. Tuberculosis affects 8-10 million people every year. It is caused due to the entry of Mycobacterium tuberculosis an aerobic intracellular pathogen into the respiratory route. Body develops cell mediated immune response when the alveolar macrophage initiates the phagocytosis of the mycobacterium. As a result of this Lymphocytes and activated macrophages triggers a granulomas formation. In some cases the body's immune response destroys the bacteria inside the granulomas by production of cytokines by T Lymphocytes, which activates the macrophages. However in most cases bacteria stays inside this granulomas and later after several years when the immune response in the granulomas fails its get reactivated and travel to different location through the blood stream. Due to this the macrophages forms epithelioid cells and multi nucleate giant cells as a result of the release of cytokines from the allergic T lymphocytes. In this stage the cytotoxic T cells targets the macrophages which consist of the bacterial antigen. Tissue damage and other characteristics develop upon triggering of macrophages by the cytokines.
Multiple sclerosis is an autoimmune disease that causes demyelination in the central nervous system. The disease is caused due to the combination of genetic and environmental factors. The prevalence of the multiple sclerosis is approximately about 1.1 and 2.5 million cases. Multiple sclerosis is inherited in a non-mendelian mode of inheritance. The concordance rate of multiple sclerosis in the family members were identified through twin studies, in monozygotic twins the prevalence rate was 25.3%, in dizygotic twins it was 5.4% and in non twin siblings it was 2.9% of prevalence rate.
Two candidate regions have been associated with the progression of multiple sclerosis namely HLA-DRB1 and IL7R (CD127) by genome wide association studies. The main characteristic feature of the disease is the development of lesions in the white matter of the nervous system. These lesions destroy the myelin sheaths which are required by the neurons for transmitting signal impulses. An inflammation is also developed in the nervous system upon entry of the T-cells through the blood-brain barrier. Usually the T-cells cannot enter the blood-brain barrier unless it is been affected by some pathogens. T-cells are locked inside this barrier and T-cells wrongly mistakes myelin as foreign substance and generate the inflammation inside the central nervous system. However it is still unclear that whether the inflammation or demyelination occurs first in the pathogenesis of the disease.