Page 588 - Clinical Immunology_ Principles and Practice ( PDFDrive )

564 ParT FOur Immunological Deficiencies

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long been an association with opportunistic infections. Beyond a clinical response was not associated with a reduction in plasma
its role in pulmonary surfactant homeostasis, the GM-CSF or BAL concentrations of anti–GM-CSF autoantibodies, thereby
receptor is widely expressed on immune cells, including neu- providing possible support for the former mechanism. 20,21
trophils, monocytes, DCs, megakaryocytes, and erythrocyte B-cell–targeted therapy using the anti-CD20 chimeric monoclonal
progenitor cells, and influences cell differentiation, proliferation, antibody (mAb) rituximab has been used to treat a small number
and immune activation. GM-CSF has been shown in both humans of patients and has shown encouraging clinical results. 22
and mice to facilitate not only terminal differentiation of
monocytes to alveolar macrophages but also innate immune ANTI–IFN-γ AUTOANTIBODIES AND
responses, primarily via induction of transcription factor PU.1. SUSCEPTIBILITY TO INTRACELLULAR PATHOGENS
Cells isolated from bronchoalveolar lavage (BAL) fluid from
patients with autoimmune PAP show decreased PU.1 messenger IFN-γ, produced predominantly by activated Th1 cells and natural
RNA (mRNA), which is thought to be central to the pathogenesis killer (NK) cells, is central to host defense against intracellular
of PAP. PU.1 has been shown to regulate Toll-like receptor (TLR) pathogens (Chapter 26). The IFN-γ receptor (IFN-γR), expressed
signaling, adhesion, phagocytosis, and microbicidal activity, thus primarily on monocytes, is composed of two subunits in duplicate,
providing a mechanism for the increased infection susceptibility IFN-γR1 and IFN-γR2. Binding of IFN-γ to its receptor leads to
that is observed in PAP. Beyond the macrophage, defects have Janus kinase 2 (JAK2) and then JAK1 phosphorylation on the
also been shown in neutrophil adhesion, phagocytosis, oxidative intracellular portions of IFN-γR2 and -1, respectively. Subsequent
burst, and bacterial killing from both the blood of human patients STAT-1 docking, phosphorylation, homodimerization, and nuclear
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with PAP and GM-CSF mouse bone marrow. 15 translocation lead to transcription of IFN-γ responsive genes.
Patients with acquired PAP are vulnerable to typical respiratory Macrophage activation, differentiation, and elaboration of inflam-
pathogens as well as opportunistic infections. Although the high matory mediators, such as tumor necrosis factor-α (TNF-α) and
incidence of respiratory infections may be partially attributable to IL-12, ensue. Defects in the IFN-γ–IL-12 axis lead to mendelian
their underlying chronic lung disease, the opportunistic infections susceptibility to mycobacterial disease as well as those caused
are generally caused by organisms controlled by macrophages, by other intracellular pathogens, including listeriosis, salmonel-
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including Nocardia, Histoplasma, nontuberculous mycobacteria, losis, histoplasmosis, melioidosis, and penicilliosis. The list of
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and Cryptococcus. Although Witty et al. reported eight cases genetic mutations involving this pathway that result in increased
of PAP and Mycobacterium avium complex cultured from BAL susceptibility to mycobacteria or other intracellular pathogens
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fluid, these patients did not receive antimycobacterial drugs and continues to expand and, to date, includes mutations in IFN-γR1,
appeared to fare no worse. Furthermore, most of these infections IFN-γR2, STAT1, IL-12p40, IL-12Rb1, nuclear factor-κB (NF-κB)
were described before the recognition of anti–GM-CSF autoan- essential modulator (NEMO), IFN regulatory factor (IRF) 8,
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tibodies as being causal, so these reports may be confounded by and IFN-stimulated gene (ISG) 15. Neutralizing autoantibodies
heterogeneity within the underlying diagnosis. against IFN-γ represent an alternative mechanism by which the
Extrapulmonary infections have been observed with some IFN-γ–IL-12 metabolic pathway is disrupted, with the first cases
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frequency, which could be ascribed to the systemic effects of described in 2004 (Fig. 40.2). We reported 85 patients identified
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anti–GM-CSF autoantibodies identified in serum. In support in a 6-month period, with over 130 patients reported to date, 8-12
of this systemic effect, several case reports describe patients with and this suggests that immunodeficiency caused by anti–IFN-γ
PAP who had extrapulmonary infections, including cases of autoantibodies is probably underappreciated.
central nervous system (CNS) Nocardia infection, septic arthritis, The infections in patients with anti–IFN-γ autoantibodies
perinephric abscess, and Nocardia dissemination to skin; CNS mimic many of those seen in patients with inborn errors in the
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Aspergillus and Proteus; and disseminated histoplasmosis. IL-12–IFN-γ signaling pathways and include mycobacterial,
Recently, a few case series have reported opportunistic infections particularly nontuberculous environmental mycobacteria,
associated with high-titer neutralizing anti–GM-CSF autoantibod- nontyphoidal Salmonella, Penicillium, Histoplasma, Cryptococcus,
ies without concurrent PAP. Anti–GM-CSF antibodies have been Burkholderia pseudomallei, and additionally varicella-zoster virus
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reported in previously healthy adults uninfected by HIV who (VZV), both dermatomal and disseminated. Infections have
had cryptococcal meningitis specifically caused by Cryptococcus been noted in all organ systems, although lymph nodes, skin,
gattii. 17,18 Neutralizing anti–GM-CSF autoantibodies were also soft tissue, and bone appear to be preferentially affected. Up to
found in five of seven patients with disseminated/extrapulmonary 50% of patients develop sterile reactive dermatoses, most com-
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Nocardia infections. However, it remains to be seen if these monly neutrophilic dermatosis, but also erythema nodosum,
infections are the only manifestations in these patients or they pustular psoriasis, and exanthematous pustulosis.
may eventually develop PAP as seen in the two of seven cases Although patients with mendelian defects tend to present
of cryptococcal meningitis associated with anti–GM-CSF in childhood, all reported cases of patients with anti–IFN-γ
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autoantibodies. Why the same autoantibody may have different were previously healthy adults, the vast majority of whom
clinical phenotypes is unknown. Opportunistic infections have were Asian-born Asians. A recent association with human leu-
not been reported as a complication of congenital PAP. Reasons kocyte antigen–antigen D related (HLA-DR)*15:02/16:02 and
for this could include the extreme rarity of this condition or HLA-DQ*05:01/05:02 was shown in 78 patients with anti–IFN-γ
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limited opportunity for exposure to environmental opportunists autoantibodies, further implicating a genetic predisposition to
as a result of medical debilitation. development of disease. However, no familial clustering has been
Treatment includes whole lung lavage to evacuate the pro- observed, and Asians born outside of Asia have yet to be reported
teinaceous material contained in the alveoli. Inhaled and sub- with this syndrome, suggesting complex genetics and possibly
cutaneous GM-CSF has also been effective either by saturating an environmental contribution to autoantibody pathogenesis.
the antibody or inducing tolerance. 20,21 In two large studies, one The recent report of an American-born, Caucasian female with
using subcutaneous GM-CSF and one using inhaled GM-CSF, this syndrome also adds to the complexity of its pathogenesis. 12