Auto-inflammatory diseases and genetics (SAIDs)

SAIDs

Systemic Auto-inflammatory diseases (SAIDs) have been defined as a group of mainly inherited disorders due to ‘abnormal hyper activation of the innate immune system’ (1). These conditions lack the characteristic features of an adaptive immune response, such as high titre antibodies or antigen specific T cells, usually seen in classical autoimmune diseases (2). Periodic Fever Syndromes (PFS) are a branch of conditions encompassed within SAIDs and form the generally more well-known and characterised conditions.

Periodic Fever Syndromes

It was 1997 when the term ‘auto-inflammatory disease’ was first proposed to categorise these disorders, introduced by the assignment of mutations within the pyrin gene as a cause of Familial Mediterranean Fever (3). These findings were then trailed by the identification of Tumour Necrosis Factor receptor (TNFR) mutations in the autosomal dominant disorder (TRAPS) (4). Succeeding this research, the Mendelian mode of inheritance of PFS together with genetic linkage and mapping techniques, permitted the identification of additional monogenic forms of SAIDs (5), allowing for a more ‘definite diagnosis’ (6). These findings paved the way for the heightened understanding of clinical disorders that had not been fully characterised; but also allowed for novel diseases to be identified.

The increased use of interleukin 1 blocking treatments in other diseases resembling auto-inflammatory phenotypes, has fronted the identification of diseases that respond well to such treatment but also those that do not (7) . The latter findings have also fuelled research into the discovery of novel pathways that lead to such unexplained disorders but with the auto-inflammatory phenotype. Despite the continued discovery of previously unidentified causes of auto-inflammation, an estimated 60% of such patients are not in possession of germline mutations, known to be causative of SAID (8).

Somatic mutations are mutations that occur postzygotically and are very common in certain types of cancer (9, 10); with somatic mosaicism being defined as ‘the occurrence of two genetically distinct populations of cells’ within an individual (10). Marrying the aforementioned concepts together, it is likely that patients who have such undiagnosed SAID (uSAID) with no germline mutations in genes associated with immunological conditions; harbour somatic mutations in a certain proportion of cells that cannot be identified via conventional Sanger sequencing, however recognition of such variations require exceedingly sensitive techniques such as high-throughput sequencing (11). Detection of causative mutations would not only allow for more personalised and targeted therapies and increase patient quality of life, but would also allow for the downstream pathophysiological characterisation of such conditions; aiding the further classification of auto-inflammatory disease (8).

My research is heavily based towards uncovering novel mutations in patients who have SAIDs but of unknown causes. This involves using techniques such as fluorescence activated cell sorting to obtain our cells of interest; PCR and agarose gel electrophoresis to amplify our genomic regions of interest; followed by DNA library preparation in order to prepare our samples for next-generation sequencing. Next-generation sequencing is a very advanced technique to essentially ‘read’ DNA. Using the Illumina MiSeq platform, this method produces a great amount of read depth – that is how many times each piece of DNA that I have input is read, enabling this sensitive procedure to highlight any mutations that may be present. Once I have received back this data and processed this, especially with novel mutations; it is up to me to delineate the functional consequences and define the effects of the mutation as best I can using cell culture and transfection techniques.

References

Lipsker D. The Schnitzler syndrome. Orphanet J Rare Dis. 2010;5:38.

Yao Q, Lacbawan F, Li J. Adult autoinflammatory disease frequency and our diagnostic experience in an adult autoinflammatory clinic. Semin Arthritis Rheum. 2015.

Consortium FF. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25-31.

McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133-44.

Hoffman HM, Brydges SD. Genetic and molecular basis of inflammasome-mediated disease. J Biol Chem. 2011;286(13):10889-96.

Babior BM, Matzner Y. The familial Mediterranean fever gene–cloned at last. N Engl J Med. 1997;337(21):1548-9.

Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147(3):155-74.

Pathak S, McDermott MF, Savic S. Autoinflammatory diseases: update on classification diagnosis and management. J Clin Pathol. 2017;70(1):1-8.

Konnick EQ, Pritchard CC. Germline, hematopoietic, mosaic, and somatic variation: interplay between inherited and acquired genetic alterations in disease assessment. Genome Med. 2016;8(1):100.

Freed D, Stevens EL, Pevsner J. Somatic mosaicism in the human genome. Genes (Basel). 2014;5(4):1064-94.

Campbell IM, Shaw CA, Stankiewicz P, Lupski JR. Somatic mosaicism: implications for disease and transmission genetics. Trends Genet. 2015;31(7):382-92.