Defects in intrinsic and innate immunity

# Overview
Defects in intrinsic and innate immunity can result in infection by bacteria, viruses, and fungi.

# Classification

## Bacterial and Parasitic infections

## MSMD and Viral Infections

# IRAK4 Deficiency
- IRAK4 (interleukin 1 receptor associated kinase 4) gene located on chromosome 12q12 encodes a kinase that activates NF-kappaB in both the toll-like receptor (TLR) and T-cell receptor (TCR) signalling pathways. The protein is essential for most innate immune responses.
- IRAK4 deficiency presents with recurrent noninvasive and invasive bacterial infections especially with pseudomonas aeruginosa, staphylococcus aureus and pneumococcus, and poor inflammatory response.
- Treatment includes; management of complications, antibiotic prophylaxis and pneumococcal vaccine.

# IRAK1 Deficiency
- IRAK1 (interleukin 1 receptor associated kinase 1) gene located on chromosome Xq28 encodes one of two putative serine/threonine kinases that become associated with interleukin 1 receptor (IL1R) upon stimulation. This gene is partially responsible for IL-1 induced upregulation of transcription factor NF-kappaB.
- IRAK1 deficiency can present with SLE like syndrome, autoimmunity, IgM & IgG autoantibodies, lymphocytic activation and renal disease.

# TIRAP Deficiency
- TIRAP (TIR domain containing adaptor protein) gene located on chromosome 11q24.2 encodes a toll interleukin 1 receptor (TIR) protein involved in TLR4 signalling pathway of immune system. It activates NF-kappaB, MAPK1, MAPK3 and JNK, which then results in cytokine secretion and the inflammatory response.
- TIRAP deficiency can present with disordered innate immune responses and life threatening staphylococcal disease.
- Treatment includes; prophylactic antibiotics, vaccinations and immunoglobulin replacement therapy.

# RPSA Deficiency
- RPSA (ribosomal protein SA) gene located on chromosome 3p22.1 encodes a high-affinity, non-integrin family, laminin receptor 1. This receptor has been variously called 67 kD laminin receptor, 37 kD laminin receptor precursor (37LRP) and p40 ribosome-associated protein. The level of the laminin receptor transcript is higher in colon carcinoma tissue and lung cancer cell line than their normal counterparts.
- RPSA haploinsufficiency causes isolated congenital asplenia (ICA) with life threatening bacterial infections.
- Treatment includes; pneumococcal vaccine, antibiotic prophylaxis, preemptive investigation and emperic treatment early in the course of disease.

# STAT1 GOF
- STAT1 (signal transducer & activator of transcription 1) gene located on chromosome 2q32.2 encodes a protein member of the STAT protein family. When activated, STAT family members translocate to the cell nucleus where they act as transcription activators. It is activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6 and is thought to be important for cell viability in response to different cell stimuli and pathogens.
- STAT1 GOF (gain of function) mutation can present with chronic mucocutaneous candidiasis (CMC), autoimmune thyroid & skin disease,cerebral aneurysms, squamous cell carcinoma and bone fragility.
- Treatment includes; antibiotic prophylaxis, IgG infusion, ruxolitinib and hematopoietic stem cell transplantation (HST).

# IL17F Deficiency
- IL17F (interleukin 17F) gene located on chromosome 6p12.2 encodes a protein cytokine that shares sequence similarity with IL17. It is expressed by activated T cells and stimulates the production of several other cytokines including IL6, IL8 and CSF2/GM_CSF. It also inhibits angiogensis of endothelial cells.
- IL17F deficiency can cause; recurrent mucocutaneous candidiasis, recurrent aphthous stomatitis (RAS) and enterovirus 71 (EV71) infection causing hand foot & mouth disease (HFMD).
- Treatment includes; management of the complications and immunosuppressive drugs.

# IL17RA Deficiency
- IL17RA (interleukin 17 receptor A) gene located on chromosome 22q11.1 encodes a transmembrane protein which is a ubiquitous type1 membrane glycoprotein that binds with low affinity to IL17A. IL17A and its receptor play a pathogenic role in many inflammatory and autoimmune diseases like rheumatoid arthritis.
- IL17RA deficiency is an autosomal recessive disease can present with chronic mucocutaneous candidiasis, staphylococcal infections and atopic dermatitis (AD).
- Treatment includes; antibiotic prophylaxis and immunosuppressive drugs.

# IL17RC Deficiency
- IL17RC (interleukin 17 receptor C) gene located on chromosome 3p25.3 encodes a single pass type 1 membrane protein that shares similarity with IL17RA. It is expressed predominantly in hematopoietic cells and binds with high affinity to only IL17A.
- IL17RC deficiency is associated with chronic mucocutaneous candidiasis (CMC) and rarely adolescent idiopathic scoliosis (AIS). The overexpression of IL17RC is associated with ocular sarcoidosis.
- Treatment includes; antibiotic prophylaxis and immunoglobulin therapy.

# ACT1 Deficiency
- ACT1 also called TRAF3 interacting protein2 gene located on chromosome 6q21 encodes a protein involved in regulating responses to cytokines by members of Rel/NF-kappaB transcription factor family. These factors play a central role in innate immunity in response to pathogens, inflammatory signals and stress.
- ACT1 deficiency can be associated with various autoimmune diseases including sjogren's syndrome, SLE-like nephritis and psoriasis vulgaris.

# CARD9 Deficiency
- CRAD9 (caspase recruitment domain family member9) gene located on chromosome 9q34.3 encodes a protein member of CARD family that plays an important regulatory role in cell apoptosis.
- CARD9 deficiency can present with chronic mucocutaneous candidiasis (CMC), treatment resistant cutaneous dermatophytosis and candida endophthalmitis.
- Treatment includes; supportive management, granulocyte-monocyte colony stimulating factor (GM-CSF) and hematopoietic stem cell transplantation (HST).

# Trypanosomiasis (APOL1)
- Humans are naturally resistant to infection by african trypanosome prototype, trypanosoma brucei brucei. This resistance is due to the activity of ApoL1.
- ApoL1 (apolipoprotein L-1) shares structural and functional similarities with apoptotic Bcl2 family and to kill the trypanosomes through anionic pore formation in the lysosomal membrane of the parasite.
- ApoL1 deficiency therefore leads to reduced or absent protection against trypanosoma brucei.
- African trypanosomiasis/sleeping sickness is transmitted to humans by bite of tsetse fly.
- Its clinical presentation evolves through local symptoms (trypanosomal chancre at bite site) to first stage (fever,lymphadenopathy, hepatosplenomegaly, faint rash) to  second stage (chronic encephalopathy with headache & mental changes) leading to terminal somnolent stage.
- Treatment includes; pentamidine, enflornithine, melarsoprol, suramin and nifurtimox with melarsoprol. 
- For more information on trypanosomiasis click here.

# Osteopetrosis
- Osteopetrosis/Marble bone disease/Albers-Schonberg disease is caused by failure of osteoclast development or function and mutations in atleast 10 genes have been identified as causative in humans.
- Osteopetrosis can be transmitted as autosomal recesve, autosomal dominant or X linked.
- It can present as fractures, short stature,compressive neuropathies, hypocalcemia with tetanic seizures and life threatening pancytopenia.
- Treatment is mainly symptomatic, hematopoietic stem cell transplantation (HST) increases the chances of long term survival.
- For more information on osteopetrosis click here.

# Hidradenitis Suppurativa
- Hidradenitis suppurativa/acne inversa/verneuil disease is a chronic, inflammatory, recurrent, debilitating skin disease of folliculosebaceopilus unit.
- It presents with painful, deep seated, inflamed lesions in apocrine gland bearing areas of body such as axila, inguinal and anogenital regions. They are painful or suppurating lesions including nodules, abscesses, draining sinus tracts and scarring can be observed.
- Treatment includes; topical antibiotics (clindamycin) and systemic treatments (clindamycin-rifampicin, tetracycline, ertapenem, rifampicin-moxifloxacin-metronidazole, acitretin, cyclosporin A, dapsone, isotretrinoin and infliximab).
- For more information on hidradenitis suppurativa click here.

# NBAS Deficiency
- NBAS (neuroblastoma amplified sequence) gene located on chromosome 2p24.3 encodes a protein with two leucine zipper domains, a ribosomal protein S14 signature domain & Sec39 like domain. It is thought to be involved in Golgi-to-ER transport.
- NBAS deficiency can present with recurrent infections, hypogammaglobulinemia, reduced natural killer cells, pelger huet anomaly and acute liver failure.
- Treatment includes; antipyretics, intravenous antibiotics, intravenous fluids with high glucose and lipids to prevent fulminant damage.

# RANBP2 Deficiency
- RANBP2 (RAN binding protein 2) gene located on chromosome 2q13 encodes a component of nuclear pore complex and plays a role in facilitation of import and export, sumoylation of protein cargoes, intracellular trafficking and energy maintenance.
- RANBP2 deficiency can present with acute necrotizing encephalopathy.
- Treatment includes methylprednisolone and immunomodulatory drugs may also be tried.

# IFNGR1 Deficiency
- IFNGR1 (interferon gamma receptor 1) gene located on chromosome 6q23.3 encodes the ligand binding chain (alpha) of the gamma interferon receptor. Human interferon gamma receptor is a heterodimer of IFNGR1 and IFNGR2.
- IFNGR1 deficiency is an autosomal recessive disease presenting with severe nontuberculous mycobaterial infections (mendelian susceptibility to mycobacterial infections) and helicobacter pylori infections.
- Treatment of choice includes hematopoietic stem cell gene therapy, as the recombinant interferon gamma therapy and hematopoietic stem cell transplantation were ineffective.

# IL12 & IL23 Receptor B1 Chain Deficiency
- IL12b gene located on chromosome 5q23.3 encodes a subunit of interleukin 12, a cytokine that acts on T ad NK cells and has a wide array of biological activities. This cytokine is expressed by activated macrophages that serve as an essential inducer of Th1 cells development.
- Its deficiency can lead to mycobacterial infections, takayasu arteritis, increased risk of ovarian endometriosis and increased hepatic cirrhosis in hepatitis C.

# ISG15 Deficiency
- ISG15 (interferon stimualated gene 15) gene located on chromosome 1p36.33 encodes a ubiquitin like protein that is conjugated to intracellular target proteins upon activation by INF-alpha & INF-beta. It has several functions including chemotactic activity towards neutrophils, direction of ligand target proteins to intermediate filaments, cell to cell signalling and antiviral activity during viral infections.
- ISG15 deficiency can lead to mendelian susceptibility to mycobaterial disease (MSMD) and salmonella infections.

# EVER1 Deficiency
- EVER1 (transmembrane channel like 6) gene located on chromosome 17q25.3 encodes integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. It encodes a transmembrane channel like protein with 10 transmembrane domains and 2 leucine zipper motifs.
- EVER1 deficiency is associated with epidermodysplasia verruciformis (EV) which is characterized by abnormal susceptibility to human papillomaviruses and multiple squamous cell carcinomas (SCC) of sun exposed areas of skin.

# EVER2 Deficiency
- EVER2 (transmembrane channel like 8) gene located on chromosome 17q25.3 encodes integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. it encodes a transmembrane channel like protein with 8 predicted transmembrane domains and 3 leucine zippers motifs.
- EVER2 deficiency can present with epidermodysplasia verruciformis (EV), HPV infection and head & neck squamous cell carcinomas.

# WHIM Syndrome
- WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections and myelokathexis is caused by mutation in the CXCR4 gene.
- CXCR4 (c-x-c motif chemokine receptor4) gene located on chromosome 2q22.1 encodes a CXC chemokine receptor specific for stromal cell derived factor1. The protein has 7 transmembrane regions & is located on cell surface. It acts with CD4 protein to support HIV entry into the cells & is also highly expressed in breast cancer cells.
- Treatment options include; granulocyte-colony stimulating factor (G-CSF), granulocyte-monocyte-colony stimulating factor (GM-CSF), plerixafor (AMD3100) and allogenic stem cell transplantation.

# STAT1 Deficiency
- STAT1 (signal transducer & activator of transcription 1) gene located on chromosome 2q32.2 encodes a protein member of the STAT protein family. When activated, STAT family members translocate to the cell nucleus where they act as transcription activators. It is activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6 and is thought to be important for cell viability in response to different cell stimuli and pathogens.
- STAT1 deficiency (loss of function mutation) can present with predisposition to intracellular (mycobacterial) and viral infections.

# STAT2 Deficiency
- STAT2 (signal transducer & activator of transcription 2) gene located on chromosome 12q13.3 encodes for a protein member of STAT protein family, when activated translocates to the cell necleus and act as transcription activators.In response to interferon, this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator.
- STAT2 deficiency can present with severe viral infections, including measles in children.

# IRF7 Deficiency
- IRF7 (interferon regulatory factor 7) gene located on chromosome 11p15.5 encodes IRF7. It play a role in the transcriptional activation of virus inducible cellular genes, including interferon beta chain genes. Its expression is largely restricted to lymphoid tissue.
- IRF7 deficiency can present with severe viral infections including life threatening influenza.

# CD16 Deficiency
- CD16 also called FCGR3A (Fc Fragement of IgG Receptor IIIa) gene located on chromosome 1q23.3 encodes a receptor for Fc portion of IgG, which is involved in the removal of antigen-antibody complexes from the circulation as well as other antibody dependant responses.
- CD16 deficiency presents with severe viral infections including life threatening herpes virus infections.

# MDA5 Deficiency
- MDA5 (melanoma differentiation associated gene 5) also called as IFIH1 (interferon induced helicase C domain containing prtein 1) gene located on chromosome 2q24.2 encodes a DEAD box proteins and is implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear & mitochondrial splicing and ribosome & spliceosome assembly.
- MDA5 deficiency can lead to recurrent and severe viral infections.

# Herpes Simplex Encephalitis
- Herpes simplex encephalitis is an infection of the brain parenchyma cause by a double stranded DNA virus called herpes simplex virus 1(HSV1), which gains access to human body through mucous membranes or damaged skin.
- It can present as fever, new seizures, altered mental status, focal neurological signs, CSF pleocytosis and contrast enhancing lesions on MRI.
- Treatment includes IV acyclovir for 14 to 21 days.
- For further information of herpes simplex encephalitis click here.