Defects in the migration of phagocytic cells to extravascular sites of infection can cause serious immunodeficiency. Leukocytes reach such sites by emigrating from blood vessels in a tightly regulated process (see Fig. 3.31). Deficiencies in the molecules involved in each stage of this process can prevent neutrophils and macrophages from penetrating infected tissues, and are referred to as leukocyte adhesion deficiencies (LADs). Deficiency in the leukocyte integrin common β2 subunit CD18, which is a component of LFA1, MAC1, and p150:95, prevents the migration of leukocytes into an infected site by abolishing the cells’ ability to adhere tightly to the endothelium. Because it was the first LAD to be characterized, it is now referred to as type 1 LAD, or LAD1, and is the most common LAD variant. Reduced rolling of leukocytes on the endothelium has been described in rare patients who lack the sialylLewisX antigen owing to a deficiency in the GDPfucosespecific transporter that is involved in the biosynthesis of sialylLewisX and other fucosylated ligands for the selectins. This is referred to as type 2 LAD or LAD2. LAD3 results from deficiency of Kindlin3, a protein involved in the induction of the highaffinity binding state of β integrins required for firm adhesion. Each variant of LAD has an autosomal recessive pattern of inheritance and causes severe, lifethreatening bacterial or fungal infections early in life that are characterized by impaired wound healing and, in pyogenic bacterial infections, the absence of pus formation. The infections that occur in these patients are resistant to antibiotic treatment. LAD3 is also associated with defects in platelet aggregation that cause increased bleeding.
A key step in the activation of innate immune cells, including phagocytes, is their recognition of microbeassociated molecular patterns through Tolllike receptors (TLRs; see Section 35). Several primary immunodeficiencies have been identified that are caused by defects in intracellular signaling components of TLRs. Signaling through all TLRs except TLR3 requires the adaptor protein MyD88, which recruits and activates the kinases IRAK4 and IRAK1, which are required for downstream activation of the NFκB and MAP kinase pathways (see Section 37). Autosomal recessive mutations in the genes encoding MyD88 or IRAK4 have a similar phenotype: recurrent, severe peripheral and invasive infections by pyogenic bacteria that elicit little inflammation, a situation known as a ‘cold’ infection. Note that many of the signaling functions of MyD88 and IRAK4 molecules are shared with IL1 family receptors. Thus, at least part of the immune defect in patients with inherited abnormalities in these molecules may be attributed to aberrant signaling by IL1 family members. Note also that NEMO deficiency, which impairs Bcell class switching (see Section 139), also impairs TLR and IL1 receptor family signaling through its block of normal NFκB activation. Immunodeficiency associated with defects in NEMO therefore affects both adaptive and innate immune function. Interestingly, increased viral infections are not typical in patients with MyD88 mutations, despite this protein’s role in signaling by each of the nucleic acidsensing TLRs except TLR3 (for example, TLR7, TLR8, and TLR9). This indicates that activation of interferon regulating factors (IRFs) that induce interferon responses downstream of these TLRs remains intact despite the defects in MyD88.