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Toll-Like Receptors, Myd88, IRAK-4, and NF-Kb Essential Modulator

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Toll-Like Receptors, Myd88, IRAK-4, and NF-Kb Essential Modulator Toll-Like Receptors, MyD88, IRAK-4, and NF-kB essential Modulator (NEMO) in Disease A Toll (“great”) Gene was describe in Drosophila by German scientists in which mutations caused bizarre flies! Gene encodes membrane receptors. Loss of function mutations made susceptible to fungi (Lemaitre et al. 1996). Janeway, 1989, proposed pattern recognition receptors on cells to recognize pathogen associate molecular patterns important in innate immunity. Mainly on white blood cells, macrophages, mast cells, and dendritic cells. Toll-like receptors (TLRs): TLR1- lipoproteins gram (+) org (PAM3CSK4); TLR2 –lipoteichoic acid gram (+) org (PAM3CSK4; zymosan); TLR3- RNA viruses (Poly I:C); TLR4 – LPS gram (-) org. (LPS); TLR5 – flagellin gram (-) org; TLR6 (zymosan) gram (+)org.; TLR7 – RNA viruses (CLO97); TLR8 – RNA viruses(CLO97); TLR9 – DNA viruses, bacteria, fungi; TLR10 – nonfunctional ? Picard, C., Casanova, J-L, Puel, A.: Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency. Clin. Microbiol. Rev. 2011, 24(3):490-497. TLRs1,2,4,6 located in plasma membrane directly interact with PAMPs while TLRs 3,7,8, and 9 are in lysosomes and endosomes and work on internalized viruses or intracellular endocytosed bacteria. TLR-3 abnormality leads to HSV meningitis and other viral infections. IRAK-4 Deficiency (AR) reported first in 2003 and now in 50 pts on 4 continents in 14 countries. MyD88 reported in 2008 and now 22 patients in America, Asia, and Europe. IRAK-4 or MyD88 patients are homozygous or compound heterozygotes. All Toll receptors except Toll 3 use IRAK4 and MyD88 and deficient patients don’t make IL-6 or shed CD62 ligand from PMNs on stimulation. Patients with both defects suffer invasive pyogenic bacterial infections such as meningitis (58%), sepsis (41%), arthritis (24%), osteo (13%), abscesses (24%), skin infection (35%), pneumonia (17%), ENT infections. Infections Streptococcus pneumonia (40%), Staphylococcus aureus (20%), and Pseudomonas aeruginosa (16%). Onset <2 (90%) and < 8yo with few infections after teens except ENT . One Mycobacteria avium but no other Mycobacteria. Immunologic findings include poor pneumococcal and anti A&B blood group IgG and IgM antibodies in 1/3, high serum IgE (2/3), and IgG4 (1/3), decreased IL-6, IL-8 and CRP responses. Twenty percent IRAK-4 deficient have delayed separation of umbilical cord!! Rx IVIG till 10 yrs, pen+ clotrimoxazole prophylaxis for life? Conjugated and non-conjugated vaccine hyperimmunization! Prompt IV antibiotic for invasive! XL – anhidrotic ectodermal dysplasia and with immunodeficiency due to hypomorphic mutations in NEMO with 100 patients since 2000, and IKBα mutations, have impaired antibody responses, poor IL-10 after TNFα stimulation, low CD4 and CD8 memory cells and in which 80% have sparse hair, conical teeth, lack sweat (ectodysplasin receptor defective), invasive pyogenic bacterial, mycobacterial, parasites, fungi, pneumocystis, candidiasis, sepsis, meningitis, deep abscesses. S pneumonia, S. aureus, H. influenza, M. avium, M. kansasii, serious viral HSV, CMV, etc. Rx IVIG, pen-cotimoxazole prophylaxis. Tx? Screening assays for IRAK4, MyD88 and Toll Receptors based on stimulated mononuclear cell cytokine production detected by multianalyte cytokine assays. Follow up with molecular confirmation assays. .
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