Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages

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Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of pulmonary surfactant, respiratory insufficiency, and increased infections. It occurs in various clinical settings that disrupt surfactant catabolism in alveolar macrophages, including a relatively more common autoimmune disease caused by GM-CSF autoantibodies and a rare congenital disease caused by CSF2RA mutations. Recent results demonstrate that GM-CSF is crucial for alveolar macrophage terminal differentiation and immune functions, pulmonary surfactant homeostasis, and lung host defense. GM-CSF is also required to determine the basal functional capacity of circulating neutrophils, including adhesion, phagocytosis, and microbial killing. PAP research has illuminated the crucial role of GM-CSF in innate immunity and led to novel therapy for PAP and the potential use of anti-GM-CSF therapy in other common disorders.

Introduction

Pulmonary alveolar macrophages are multifunctional tissue representatives of the bone marrow-derived mononuclear phagocyte system that serve as a first line of defense against inhaled microbial pathogens and toxins, clear inhaled debris, excess surfactant and apoptotic cells from the alveolar surface, orchestrate pulmonary inflammatory responses, and participate in wound healing and lung remodeling. A broad range of exogenous and endogenous factors interact with and modify the functions of these cells, including colony stimulating factors such as GM-CSF, M-CSF, and IL-3. GM-CSF, initially identified by its ability to stimulate the formation of neutrophil and macrophage colonies from bone marrow precursors, is now regarded as an important immunoregulatory cytokine with pleiotropic effects on myeloid cells in health and disease (reviewed in [1]) mediated through complex signaling pathways (Figure 1). The serendipitous discovery that GM-CSF deficient mice accumulate surfactant in the lungs identified the crucial role of GM-CSF in alveolar macrophage function and surfactant homeostasis (reviewed in [2]). Early studies showed that this phenotype is caused by the absence of GM-CSF in the lungs where it is required to stimulate alveolar macrophages to catabolize surfactant lipids and proteins. Subsequent studies demonstrated that GM-CSF deficient mice have increased mortality from pulmonary and systemic infections, and that myeloid cells from these mice have multiple innate immune defects (reviewed in [3]).

Pulmonary alveolar proteinosis (PAP) causes lung pathology similar to that of GM-CSF deficient mice and occurs in a heterogenous group of diseases (reviewed in [4]). While function-altering GM-CSF mutations have not been identified in humans, PAP is associated with disruption of GM-CSF signaling caused by high levels of neutralizing GM-CSF autoantibodies in autoimmune PAP or by mutations in CSF2RA, the gene encoding the GM-CSF receptor α protein in congenital PAP. Both PAP patients and GM-CSF deficient mice have increased susceptibility to opportunistic microbial pathogens and increased mortality from uncontrolled infections [5••]. Here, we review recent studies that helped elucidate the pathogenesis of autoimmune and congenital PAP, the role of GM-CSF in alveolar macrophage and neutrophil function in mice and man, and studies that implicate GM-CSF in the pathogenesis of serious inflammatory and autoimmune diseases.

Section snippets

Autoimmune PAP: an attack of adaptive immunity on innate immunity

First described by Rosen in 1958, the pathogenesis of PAP remained enigmatic for more than four decades. Following the discovery of PAP in GM-CSF deficient mice, neutralizing GM-CSF autoantibodies were detected in patients with the common clinical PAP subtype (idiopathic PAP) [6••]. These were composed of polyclonal IgG, primarily IgG1 and IgG2 with only small amounts of IgG3 and IgG4, and were highly specific for human GM-CSF recognizing multiple epitopes and binding with an affinity of 20 ± 7.5 

Congenital PAP caused by disruption of GM-CSF receptor function

GM-CSF signaling is mediated by cell surface receptors composed of a low-affinity GM-CSF-binding α chain and an affinity-enhancing β chain common to the receptors for GM-CSF, IL-3, and IL-5 [1]. Neither the α chains nor the β chains possess intrinsic signaling capacity but the β chain constitutively associates with Jak2, which is crucial for signaling. The pleiotropic effects of GM-CSF on myeloid cell survival, proliferation, differentiation, and activation appear to be mediated partly via a

GM-CSF is crucial for the terminal differentiation of alveolar macrophages

Evaluation of mice in which GM-CSF expression was normal, absent, or occurred only in the lungs revealed that pulmonary GM-CSF regulated alveolar macrophage expression of the myeloid master transcription factor, PU.1, suggesting GM-CSF was required for alveolar macrophage maturation [14••]. An alveolar macrophage cell line (mAM) derived from GM-CSF deficient mice also failed to express PU.1 and had a phenotype similar to that of primary cells from these mice (Table 1). This phenotype included

GM-CSF is a crucial regulator of myeloid cell host defense functions

Uncontrolled infection, frequently by opportunistic pathogens, account for 18% of attributable mortality in PAP patients [5••]. Similarly, GM-CSF deficient mice have increased mortality from infection and increased susceptibility to a wide range of microbial pathogens, including bacteria (Streptococcus [29], Pseudomonas a. [30], Listeria monocytogenes [31]), fungi (Pneumocystis carinii [32]), malaria (Plasmodium chabaudi [33]), virus (adenovirus [24]), and Mycobacteria (M. tuberculosis [34]) (

Manipulating GM-CSF bioactivity: potential new therapeutic applications

Studies evaluating GM-CSF deficient mice in various experimental disease models and the demonstration of increased GM-CSF levels in the corresponding human disorders have implicated GM-CSF in the pathogenesis of inflammatory and autoimmune diseases (reviewed in [39, 40•]). For example, GM-CSF deficient mice develop less-severe pathology in models of collagen-induced arthritis [41] and GM-CSF is increased in synovial fluid from patients with rheumatoid arthritis [42]. Similarly, GM-CSF deficient

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to colleagues whose work could not be cited owing to strict space limitations. Supported partly by grants from the National Heart, Lung, and Blood Institute (HL0085453 to Trapnell) and the National Center for Research Resources and the National Institutes of Health Office of Rare Diseases (RR019498 to Trapnell).

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