Meta-Biol

• Pathways

The nuclear factor kappa B (NFkB) family of transcription factors is kept inactive in the cytoplasm by the inhibitor of kappa B (IkB) family members IKBA (IkB alpha, NFKBIA), IKBB (IkB beta, NFKBIB) and IKBE (IkB epsilon, NFKBIE) (Oeckinghaus A and Ghosh S 2009). Multiple stimuli such as inflammatory cytokines, microbial products or various types of stress activate NFkB signaling leading to stimuli-induced phosphorylation of IkB molecule (Scherer DC et al. 1995; Alkalay I et al. 1995; Lawrence T 2009; Hoesel B and Schmid JA 2013). The phosphorylation of IkB proteins triggers their polyubiquitination and subsequent degradation by 26S proteasome, allowing free NFkB dimer to translocate to the nucleus where it directs the expression of target genes. Studies have identified an autosomal dominant form of ectodermal dysplasia with immunodeficiency (AD-EDA-ID) caused by a hypermorphic heterozygous mutation of NFKBIA/IKBA gene. The IKBA defects prevent the phosphorylation and degradation of IKBA protein resulting in gain-of-function condition with the enhanced inhibitory capacity of IKBA in sequestering NF?B dimers in the cytoplasm (Courtois G et al. 2003; Lopes-Granados E et al. 2008; Schimke LF et al. 2013).

The immune system is a complex network of the biological processes that provide defense mechanisms during infection or in response to an intrinsic danger signal. Compromised immune response may present itself as either overactivity or underactivity of the immune system leading to a broad spectrum of clinical phenotypes that can be categorized into four main groups - autoimmunity, immunodeficiency (ID) with a greater susceptibility to infectious diseases, hypersensitivity to compounds that are usually not harmful and malignancy. Several host conditions may cause the dysfunctional immunity. Among them are inherited and somatic mutations found in the components of immune signaling pathways. In addition to genetic defects, infection with pathogen such as human immunodeficiency virus (HIV), or interaction of immune cells with immunosuppressive drugs result in non-genetic immunodeficiencies. Age-associated alterations in immunity may also contribute to pathogenesis of immunodeficiency .

The Reactome module represents selected defects of the immune system and provides a short description of their clinical phenotypes. The module also describes functional features of defective molecules by both providing a published source for experimental functional analysis data and linking to the corresponding normal process within the Reactome database.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.