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Disorders that affect host body may have various etiologies such as environmental, genetical and immunological. Understanding the immunological basis of a disease is gaining widespread importance due to the complexity involved. One such condition is autoimmunity where host bodys self defence machinery itself attacks ultimately leading to a deleterious condition.The present description is based on a related disorder known as Lupus which falls under the category of Autoimmunity. Lupus is a chronic disease that has potential to attack skin, joints or any other organ of the body . The symptoms may continue to exist from weeks to years. Lupus is also considered as a disease of flares where the symptoms frequently worsen and subside. Here the patient could feel ill and better. Causes of Lupus: Lupus has three important causes. Firstly, lupus is believed to have some genetic relationship as some ethnic groups belonging to Native American, Native Hawaiian, or Pacific Island have increased risk. It is highly likely that there is a chance of developing the disease in one of two identical twins when it runs in certain families irrespective of history. However this aspect needs to be explored. Secondly, environment has vital clues. Ultraviolet rays from the fluorescent light bulbs, sun, certain sulfa drugs that increase the sun-sensitivity, like Bactrim and Septra (trimethoprim-sulfamethoxazole); sulfasalazine (Azulfidine); diuretics. Similarly, sun-sensitizing tetracycline drugs such as minocycline (Minocin), penicillin or other antibiotic drugs such as: amoxicillin (Amoxil), cloxacillin (Cloxapen).The other contributing agents are infections, viral fever, fatigueness,an injury, emotional stress, or other life complications such as surgery, physical harm, pregnancy, or giving birth. The third important cause thought to be central for development of lupus is hormonal overproduction. Women are considered to have increased risk for lupus as estrogen production is more compared to men. There are different types of lupus reported to date. They are Systemic lupus erythematosus (SLE) which affects major organs such as heart, lungs, kidneys, and brain.
Discoid lupus erythematosus affects skin. Drug-induced lupus induced by a particular medication . Next, there is a need to explore whether Lupus is a genetic disease. It was reported that Lupus is not hereditary in nature as the disease passes from the parent to the offspring . But when there is a predisposition to the disease development that passes from parent to the child, then lupus becomes hereditary . It means it has a dual role to play. However, every child with a parent who has lupus may not develop the disease. Children could develop the lupus irrespective of family history.
To this end researchers have investigated the familial roles of Lupus. The type of research that has gained importance is family linkage study to confirm previous genetic association, to examine their relative contributions, and to identify new susceptibility loci (Arnett, 2000). This was revealed when alleles belonging to Major Histocompatibility Complex (MHC) class II were found mediate specific T lymphocyte initiated pathogenic autoantibodies that produce features similar to other autoimmune diseases (Arnett, 2000). A deficiency in hereditary complement components is believed to have strong association with lupus (Arnett, 2000). Heterozygous complement deficiencies have moderate susceptibility effects compared to homozygous deficiencies that are considered as powerful risk factors (Arnett, 2000). This information may clearly indicate that family linkage study has benefits to dissect the relationship between the genes and disease susceptibility. Further, modern scientists have employed a method of Microarray technology to study gene expression with reference to Lupus. They have coupled data analysis using sophisticated statistical algorithms to better understand the pathological basis of a disease (Crow & Wohlgemuth, 2003).This was done by gathering the data from various laboratories and documenting the feasibility of analysis of heterogeneous populations of peripheral blood mononuclear cells from patients with systemic lupus erythematosus (Crow & Wohlgemuth, 2003).
Here, interferon-induced gene expression was found to be more significant. This has indicated that circulating interferon-alpha in the blood of patients with active lupus has clues to the interferon pathway in the hierarchy of gene expression pathways implicated in systemic autoimmunity (Crow & Wohlgemuth, 2003). Therefore, the method of studying gene expression patterns have potential to furnish information regarding the linkage.
Further, Geneticists have conducted genome wide scans with the intention of exploring the genetic diversity associated with Lupus. They have identified different genes involved in the disease development. The genes tend to exhibit variation depending on a patients ethnicity or the disease symptoms that enhance the risk . The genes identified in this context are FcgammaRIIA; FcgammaRIIIA; complement components C2, C4 and C1q; PDCD-1; and HLA-DR . Single Nucleotide Polymorphisms (SNPs) studies in association with multiplex family research have been conducted that revealed lupus hot spots as candidate genes . A Multiplex family provides information on the inheritable mode of lupus, or lupus that is passed on genetically . There is a need to know about the hot spots for lupus genes which are under investigation . They are 2q34 AfricanAmerican patients with renal disease, 2q37 European-American families, PDCD7 5p15 multiple family members with rheumatoid arthritis, 10q22 European-American patients with renal disease ,11p13 African-American patients,11q14 African-American patients with hemolytic anemia ,12q24 Hispanic Patients . These genes have a function of increasing the susceptibility to a specific racial /ethnic population (Lauwerys & Wakeland, 2005). Screening studies have revealed the reliability of several loci containing potential targets (FcgammaRIIa, PTPN22, PD-1, IL-10) for physiopathological research and therapeutic interventions. (Lauwerys & Wakeland, 2005). Animal screening studies involving congenic mice with a normal genetic background and one single disease-associated locus have also contributed to the understanding the genetics of Lupus especially Lupus nephritis (Lauwerys & Wakeland, 2005). The current status of lupus is that nearly one hundred genetic risk factors have been defined in systemic lupus erythematosus through a combination of case studies, linkage analyses of multiplex families, and case-control analyses of single genes. In addition, the discovery of genes earlier is having better future implications. These include genes encoding human leukocyte antigen-DR, Fc gamma receptor 3A, protein tyrosine phosphatase nonreceptor 22, cytotoxic Tlymphocyte associated antigen 4, and mannose-binding lectin (Sestak et al., 2007).
The next aspect of Lupus is regarding the screening procedure. This entails familial clustering and data from studies that could provide direction for searching for the putative loci (Heward & Gough, 1997). Here, tests such as candidate gene approach in population-based case-control studies and entire genome screening in families could help identify susceptible genes in a number of autoimmune disorders like Lupus (Heward & Gough, 1997). In addition, association studies using family background also helps in identifying the susceptible candidates through linkage and mapping (Heward & Gough, 1997).This could also enable to identify primary etiological mutations that might be connected to Lupus (Heward & Gough, 1997).Recently, a method of genome-wide associations scans (GWAS) was employed to identify confirmed and candidate risk variants which are in agreement with the statistical criteria(Graham et al, 2009). This study enabled to identify 17 common SLE risk variants, four candidate variants that could be grouped under the category of a confirmed SLE risk locus (Graham et al, 2009).
Similarly, a method of initial pathway analyses enabled to identify 17 confirmed SLE risk alleles indicating an important role for B-cell signalling and development, signaling through toll-like receptors 7 and 9, and neutrophil function (Graham et al, 2009). These tests have implications to screen large number of population suspected for Lupus. A random cohort study in association with genetic linkage analysis, strong family history, data gathered from different clinical settings would ensure rapid identification of susceptible candidates. Further, genes having a suspicious role in the development of lupus may often produce controversial results.
Genome wide screening as mentioned above may help to solve the mystery involved in the identification of a reliable candidate locus. Here, It can be inferred that a thorough pedigree analysis reflecting the maternal sibling relationship has vital role with genome wide scan process in the development of Lupus.
Conclusion
Lupus presents one of the serious autoimmune disorders with the potential of inducing multiorgan symptoms. The important causes originating from genetic, environment and hormone are increasing the complexity of the Lupus. Whether lupus is a genetic disorder or not has become the active area of research to explore the unknown facts. This prompted the researchers to undertake many association studies which ultimately led to the identification of many loci on genes.The hereditary role of lupus has come into light due to information from family linkage studies.However,Lupus could also predispose the individuals regardless of the family history. The deficiency in the complement system in homozygous and heterozygous forms has been implicated to play vital role in contributing to the risk (Arnett, 2000). Hence, understanding the complement pathway is essential. Similarly, interferon-induced gene expression patterns as revealed from circulating interferon-alpha levels in the blood of patients with active lupus has vital role to play in the disease development (Crow & Wohlgemuth, 2003). Lupus is now believed to have genetic diversity due to the identification of some of the genes like FcgammaRIIIA; complement components C2, C4, 2q34, PDCD7, 5p15, 12q24 etc. (Lauwerys & Wakeland, 2005). These genes have made specific racial /ethnic populations more vulnerable to Lupus. Microarray ananlysis and genome wide scans have contributed to the greater understanding of the genetics of Lupus. This has led to the identification of hot spots that are considered as ideal targets for SNP studies. This clearly indicated the need of multiplex family research.Since Lupus has a multi organ etiology, the above information could serve as a reliable tool to dissect the relationship between other autoimmune diseases and genes. There is a need to implement the above mentioned genetic strategies in an evidence based manner to obtain betterresults.This could better help in devising strong therapeutic inventions to alleviate the Lupus associated disorders in the society.
References
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Is Lupus hereditary? 2009 Micro Nutra Health Journal. Web.
Arnett, F.C. (2000). Genetic studies of human lupus in families. Int Rev Immunol, 19, 297-317.
Crow, M.K, & Wohlgemuth, J. (2003). Microarray analysis of gene expression in lupus. Arthritis Res Ther, 5, 279-87.
Genetic Diversity & Lupus. (n.d). Web.
Lauwerys, B.R & Wakeland, E.K. (2005). Genetics of lupus nephritis. Lupus,14,2-12.
Sestak,A.L., Nath, S.K., Sawalha, A.H., Harley, J.B.(2007). Current status of lupus genetics. Arthritis Res Ther, 9, 210.
Heward, J & Gough, S.C. (1997). Genetic susceptibility to the development of autoimmune disease. Clin Sci (Lond), 93,479-91.
Graham, R.R., Hom, G., Ortmann, W., Behrens, T.W. (2009). Review of recent genome-wide association scans in lupus. J Intern Med, 265, 680-8.
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