Table 5.13 Common Inherited Immune Deficiencies of Phagocytic Leukocytes and the Complement System
C2,C4deficiencyDefectiveclassicalpathwayactivation;resultsinreducedresistancetoinfectionandreducedclearanceofimmunecomplexes
ModifiedinpartfromGallinJI:Disordersofphagocyticcells.InGallinJI,etal,editors:Inflammation: basic principles and clinical correlates, ed2,NewYork,1992,RavenPress,pp860–861.
appears at sites of infection if the initial neutrophil defense is inadequate. These collections of activated macrophages form granulomas in an effort to wall off the microbes.
Chédiak-Higashi syndrome is characterized by defective fusion of phagosomes and lysosomes, resulting in defective phagocyte function and susceptibility to infections. The main leukocyte abnormalities are neutropenia, defective degranulation, and delayed microbial killing. The affected leukocytes contain giant granules, which are readily seen in peripheral blood smears and are thought to result from aberrant phagolysosome fusion. In addition, there are abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (causing bleeding disorders). The gene associated with this disorder encodes a large cytosolic protein called LYST, which is believed to regulate lysosomal trafficking.
TLR defects are rare but informative. Mutations in TLR3, a receptor for viral RNA, result in recurrent herpes simplex encephalitis, and mutations in MYD88, an adaptor protein needed for signaling downstream of multiple TLRs, are associated with destructive bacterial pneumonias.
Deficiencies Affecting the Complement System
Deficiency of several complement components have been described, with C2 deficiency being the most common. Deficiencies of C2 or C4, early components of the classical pathway, are associated with increased bacterial or viral infections; however, many patients are asymptomatic, presumably because the alternative complement pathway is able to control most infections. Surprisingly, in some patients with C2, C4, or C1q deficiency, the dominant manifestation is an SLE-like autoimmune disease, possibly because these factors are involved in clearance of immune complexes. Deficiency of C3 is rare. It is associated with severe pyogenic infections as well as immune complex–mediated glomerulonephritis. Deficiency of the late components C5 to C9 results in increased susceptibility to recurrent neisserial (gonococcal and meningococcal) infections, as Neisseria bacteria have thin cell walls and are especially susceptible to the lytic actions of complement.
Defects in complement regulatory proteins result in excessive inflammation or cell injury. A deficiency of C1 inhibitor (C1 INH) gives rise to an autosomal dominant disorder called hereditary angioedema, C1 INH is an inhibitor of many proteases, including kallikrein and coagulation factor XII, both of which are involved in the production of vasoactive peptides such as bradykinin. Therefore, defective C1 INH activity leads to over-production of bradykinin, which is a potent vasodilator. Affected patients have episodes of edema affecting skin and mucosal surfaces such as the larynx and the gastrointestinal tract. Acquired deficiencies of other complement regulatory proteins are the cause of paroxysmal nocturnal hemoglobinuria (Chapter 12), while some cases of hemolytic uremic syndrome (Chapter 14) stem from inherited defects in complement regulatory proteins.
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Thesediseasesarecausedbyinheritedmutationsingenesinvolvedinlymphocytematurationorfunction,orininnateimmunity.