Page 878 - Clinical Immunology_ Principles and Practice ( PDFDrive )

850 Part Seven Organ-Specific Inflammatory Disease

this antibody probably is not specific for neutropenia, since it is
also present in patients with autoimmune disease who do not
have neutropenia.
Patterns of Autoantibody Specificity
Isoimmune neonatal neutropenia is associated with maternal
IgG iso- or autoantibodies that can be generated in response to
each of the polymorphic alloantigens noted above, particularly
polymorphisms affecting FcγRIIIb.
Platelets with bound IgG Macrophage with FcRγIIA receptor Immune neutropenia in childhood is most commonly
FIG 62.3 Antibody-Bound Platelets Are Cleared From the associated with IgG directed against the autoantigens HNA-1a
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Circulation by Binding of the Fc Domain of Immunoglobulin and/or HNA-1b. Sera from affected patients often also bind
G (IgG) to FcγIIIA Receptors on Macrophages and Other Cells. (albeit more weakly) to neutrophils expressing the alternative
The cross-linking of the macrophage receptors sets off a cascade allele, and in some series, more than half the patients with this
of internal signaling that leads to increased expression of the entity were shown to produce antibodies capable of binding to
inhibitory FcγIIB receptors (not shown). nonpolymorphic elements within FcγRIIIb. Using monoclonal
antibody (mAb)–specific immobilization of granulocyte anti-
gens (MAIGA) to search for antibodies directed against other
neutrophil surface molecules, more complex patterns can be
recognized. In one study, autoantibodies against FcγIIIb were
Antibody Specificity seen in 27%, against CD11b/CDI8 (CR3) in 21%, against CD35
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The most important target for antibody responses is the Fcγ (CR1) in 14%, and FcγRII in 2% of patients’ sera. Prognostically,
receptor IIIb (FcγRIIIb), a low-avidity granulocyte-specific Fcγ patients with antibody responses confined to HNA-1a and/or
receptor that binds IgG immune complexes (Fig. 62.3). This cell HNA-1b are more likely to have uncomplicated, self-limiting
surface protein, a glycosyl phosphatidylinositol-linked variant disease; patients with specificity for nonpolymorphic determinants
of CD16 selectively expressed on neutrophils, contains several on the FcγRIIIb molecule and other antigens more often have a
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highly immunogenic polymorphisms. 24 generalized immune disorder and more persistent neutropenia.
Human neutrophil antigen 1a (HNA-1a) and HNA-1b (previ- Although antineutrophil assays are not highly quantitative, a
ously designated NA1 and NA2) are two related polymorphic recent retrospective study has suggested that patients with low
forms of FcγRIIIb. Antigenic differences are attributed to a cluster levels of ANAs may have a more favorable long-term prognosis. 28
of five base substitutions, all found within exon 3. The two In adults, it is often difficult clinically to distinguish immune
products can be distinguished because two of the base substitu- neutropenia from nonimmune idiopathic neutropenia. Conse-
tions in HNA-1a disrupt sites of N-linked glycosylation, thereby quently, the sensitivity and specificity of antibody assays in this
lowering the size of the protein by ~30 000 Daltons (Da). The setting are uncertain. In general, antibodies against HNA-1a or
frequency of the gene for HNA-1a (FCGR3B) varies from 0.3 HNA-1b are less common, and antibodies against surface recep-
to 0.55 in different ethnic groups. tors, such as CD11b/CD18 (CR3), are more common in older
HNA-1c (previously designated SH) is another immunogenic children and adults than in young children.
20
21
polymorphism related to FcγRIIIb. This antigen, present in 5% Sera from patients with Felty syndrome and T-LGL leukemia
of northern Europeans, is attributable to an amino acid poly- are often positive in ANA assays. Interpretation of these results
morphism at position 266 in a (reduplicated) copy of the HNA-1b is complicated by the high incidence of nonspecific immune
allele of FcγRIIIb. complexes in these populations, which may bind nonspecifically
FcγRIIIb-null phenotype, present in 0.1% of the northern through Fc and complement receptors to the neutrophil surface.
European population, occurs in individuals homozygous for an Indeed, because it is difficult to distinguish these two types of
extensive gene deletion involving all of FcγRIIIb. Because affected binding, the incidence of “true” ANAs in these syndromes remains
individuals have never been exposed to endogenous FcγRIIIb, uncertain. Detectable antineutrophil antibodies are low in titer or
they often develop a broad antibody response after neutrophil absent in most patients carefully studied with either diagnosis. 20,21
exposure through transfusion or pregnancy.
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Other HNAs have also been identified. Perhaps most Impact of Antibodies and Immune Complexes on
clinically relevant is HNA-2a (previously NB1), a neutrophil Neutrophil Survival
glycoprotein designated CD177. Antibodies against this target There is good experimental evidence that both ANAs and immune
have been reported in isoimmune and autoimmune neutropenia. complexes can induce neutropenia in vivo. The relative importance
HNA-3a (previously 5b) and HNA-4a (previously MART), an of reversible sequestration and neutrophil destruction in inducing
epitope on CD11b, are also immunogenic, but antibody formation neutropenia varies with the experimental model, the character
against these is seen primarily in heavily transfused individu- of the antibody/immune complex, spleen size, and presumably
als and not in autoimmune neutropenia. As described below, other factors as well.
individuals with chronic immune neutropenia may develop The detection of antineutrophil antibodies in serum, however,
antibodies against other surface antigens, including CD11b/CDI8 does not automatically predict accelerated immune clearance of
and CD35. 26 neutrophils in vivo. Some antibodies bind well to neutrophils
Using a sophisticated antigen discovery strategy, patients under in vitro assay conditions, without provoking neutrophil
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with Felty syndrome were found to have a high incidence of destruction in vivo. In part, this reflects the inability of these
antibodies against an intracellular antigen eukaryotic elongation crude assays to distinguish effective from ineffective binding of
factor 1A-1 (eEF1A-1). Although the finding has been confirmed, immunoproteins.