Concise Clinical Review
A Concise Review of Pulmonary Sarcoidosis
Robert P. Baughman1, Daniel A. Culver2, and Marc A. Judson3
1Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio;2Respiratory Institute, Cleveland Clinic Foundation,
Cleveland, Ohio; and3Department of Medicine, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston,
treatment. In the area of etiopathogenesis, we now have a better
understanding of the immune response that leads to the disease as
as a cause for sarcoidosis. Although none of these potential causes
has been definitely confirmed, there is increasing evidence to
support that one or more infectious agents may cause sarcoidosis,
although this organism may no longer be viable in the patient. The
diagnosis of sarcoidosis has been significantly aided by new tech-
shown to increase the yield of needle aspiration of mediastinal and
hilar lymph nodes. The positive emission tomography scan has
involvement not appreciated by routine methodology. It has also
the anti–tumor necrosis factor antibodies, have changed the ap-
proach to refractory sarcoidosis. There is increasing evidence that
the clinician can identify which patient is most likely to benefit from
patient with sarcoidosis, including fatigue and sarcoidosis-associated
pulmonary hypertension. There have been several recent studies
demonstrating treatment options for these problems.
Keywords: mycobacterium; HLA; Lo ¨fgren syndrome; infliximab; pul-
Sarcoidosis is a granulomatous disease of unknown etiology that
affects people throughout the world (1). Over the past few
years, there have been advances in our understanding of
sarcoidosis. These include observations about the etiopatho-
genesis, diagnosis, and treatment of the disease. In this review,
we discuss observations in these various areas.
ETIOLOGY AND PATHOGENESIS
The immunopathogenesis of sarcoidosis is not completely un-
derstood, but there has been tremendous progress in the past
decade. Most evidence suggests that the development of the
disease is similar to other granulomatous diseases of known
cause, such as chronic beryllium disease. That is, some anti-
gen(s) enter the host and are phagocytosed by antigen-presenting
cells (APCs), predominantly macrophages or dendritic cells. The
APCs process the antigen and subsequently present it via human
leukocyte antigen (HLA) class II molecules to a restricted set
of T-cell receptors on naive T lymphocytes, primarily of the
CD41class. Induction of the immune response depends on
intact cell-mediated immunity, as evidenced by the phenome-
non of reactivation sarcoidosis coinciding with immune recon-
stitution during treatment for HIV (2). The immune reaction
begets polarization of the T lymphocytes to a Th1 phenotype,
followed by cellular recruitment, proliferation, and differentia-
tion leading to formation of the sarcoid granuloma. A panoply
of cytokines and chemokines has been reported in association
with sarcoidosis, but the relative importance of most of them is
The pathogenesis of sarcoidosis seems to involve the interplay
of antigen, HLA class II molecules, and T-cell receptors (3). It
is likely that specific combinations of these three facets are
required for sarcoidosis to develop. If this scenario is correct, the
pathophysiology of sarcoidosis depends on genetics that deter-
mine specific HLA polymorphisms, exposures in the form of
putative antigens, and T-cell responses that may be genetically
programmed but may also involve memory from previous
antigen exposure. This schema also suggests that there may be
multiple causes of sarcoidosis, each requiring a specific arrange-
ment of antigen, HLA molecule, and T-cell receptor (Figure 1).
Investigation of the genes involved in sarcoidosis has focused
on the HLA genes (1). For example, analysis of patients enrolled
in a multicenter epidemiologic study of sarcoidosis in the United
States (A Case Controlled Etiologic Study of Sarcoidosis)
demonstrated that carriage of HLA-DRB1*1101 and HLA-
DPB1*0101 alleles are risk factors for the disease (4). A family-
based association study in black U.S. patients with sarcoidosis
certain HLA-DQB1 alleles (5). The phenotype and outcome of
sarcoidosis is probably influenced strongly by HLA genes. For
example, carriage of HLA-DRB1*03 in Swedish subjects with
sarcoidosis is strongly associated with the development of Lo ¨fg-
ren syndrome and also with disease resolution (6, 7). Similarly,
responsible allele because of its strong linkage to HLA-DRB1.
These studies have highlighted the issues of population stratifi-
studies of sarcoidosis.
Genome-wide approaches have identified non-HLA candi-
date susceptibility genes. For example, a family-based study in
affected German families led to the discovery of a mutation in
that may explain 23% of the attributable risk in that population
(9, 10). Analysis of the same gene in black U.S. subjects failed to
reveal any role for BTNL2 but did confirm its association with
sarcoidosis in white subjects (11). In contrast, a genome-wide
sibling-based microsatellite linkage analysis in 229 families of
black U.S. patients most strongly implicated regions in chromo-
(Received in original form June 6, 2010; accepted in final form October 29, 2010)
Supported by National Institutes of Health grant HL081538 (D.A.C.).
Correspondence and requests for reprints should be addressed to Robert P.
Baughman, M.D., 1001 Holmes, Eden Avenue, Cincinnati, OH 45267-0565.
Am J Respir Crit Care Med
Originally Published in Press as DOI:10.1164/rccm.201006-0865CI on October 29, 2010
Internet address: www.atsjournals.org
Vol 183. pp 573–581, 2011
somes 5p and 5q (12). More recently, a genome-wide association
study in German subjects suggested a role for mutations in the
annexin1 gene (13); however, this observation has not yet been
confirmed. Using a different technique of biallelic marker
scanning, linkage peaks in chromosomes 12p and 9q were also
identified (14). A key aspect of genome-wide studies is the
requirement for adequate fine-mapping and functional studies
after the initial scan to define the biologic relevance of the
The granuloma in sarcoidosis is characterized by a core of
monocyte-derived epithelioid histiocytes and multinucleate
giant cells with interspersed CD41T lymphocytes. A minority
of cells in or near the granuloma are CD81T lymphocytes,
fibroblasts, regulatory T cells, and B lymphocytes. The T-cell
response is biased toward a Th1 phenotype, with important
roles for IFN-g and interleukin-12 (15). A variety of chemo-
kines and cytokines have been associated with the granuloma-
tous response in sarcoidosis, including tumor necrosis factor
a (TNF-a) (16, 17). The importance of TNF in sarcoidosis has
been validated by studies documenting effectiveness of biologic
TNF antagonists in sarcoidosis in treating some patients with
Rather than focusing on candidate mediators, a hypothesis-
free approach to understanding the granulomatous response has
been reported recently. Using a bioinformatic analysis, Crouser
and colleagues analyzed global gene expression networks in
sarcoidosis and control lung tissue and lymph nodes (19). They
activator of transcription-1 (STAT1) as the most significantly
associated with sarcoidosis. Because STAT1 is the signaling
target of IFN-g, this analysis confirmed the importance of the
Th1-dominated lymphocyte response. It also allowed identifica-
tion of novel gene products tightly associated with sarcoidosis,
study in peripheral blood cells used the same techniques and also
implicated STAT-1 signaling pathways as a central feature of
sarcoidosis, the difficulties with animal models and lack of a de-
fined antigen, inductive research designs and bioinformatic
techniques may play important roles in future pathophysiologic
Sarcoidosis probably requires exposure to one or more
exogenous antigens. Epidemiologic data, including reports of
case-clustering, increased susceptibility with certain occupa-
tions, and transmissibility via transplant, all support this theory
(21, 22). Infectious agents have long been suspected as possible
causes of sarcoidosis, but early studies failed to yield convincing
support for various organisms. Using molecular techniques,
there are now accumulating data suggesting that bacteria, such
as mycobacteria or Propionibacterium acnes, may contribute to
the disease (23). It is quite possible that the triggering antigen
varies depending on ethnicity, geographic location, and in-
dividual genetic background.
Although Mycobacterium tuberculosis does not seem to be
the etiologic trigger for sarcoidosis, there is increasing evidence
for mycobacteria as a cause of at least some cases of sarcoidosis.
A key observation was the finding that the protein mycobacte-
rial catalase-peroxidase (mKatG) was present in sarcoidosis
tissue, had the same physicochemical properties as the Kveim-
Siltzbach reagent, and was associated with the presence of
humoral immunity in the same subjects (24). Subsequent studies
have demonstrated a T-cell response to mKatG by the periph-
eral blood lymphocytes of patients with sarcoidosis (25, 26).
Analogous to infection with tuberculosis, even more robust
responses to mKatG have been found in T cells obtained by
bronchoalveolar lavage from patients with sarcoidosis, but not
other lung diseases, and more strongly in active disease (25, 27).
Sequence analysis of nucleic acids in granulomas suggests that
the putative mycobacterium has closer homology to the M.
tuberculosis family rather than to other nontuberculous myco-
Importantly, T-cell responses are not limited to the mKatG
protein alone but can also be demonstrated for mycolyl
transferase antigen 85A, mycobacterial superoxide dismutase,
and early secreted antigen target 6 in the peripheral blood and
bronchoalveolar lavage (BAL) (29, 30). One interpretation of
these observations is that the agent causing sarcoidosis for
some patients may be more than just a single, poorly degrad-
able peptide; these observations do not exclude the possibility
of an intact organism as the cause for the disease. However, it
is not required that the organism causing sarcoidosis be viable.
The Kveim-Siltzbach agent has no observed viable organism
present, yet it will induce a granulomatous response in the
majority of patients with sarcoidosis. Moller postulated that
the antigen(s) from this mycobacterium could be released
during the death of the organism, with a complex of host and
mycobacterial proteins in response to the infection leading to
sarcoidosis (31). He also suggests that the failure to clear these
antigen/protein complexes in some patients could lead to
with formation of granuloma and subsequent
resolution or persistence of disease. HLA 5 human
leukocyte antigen; IFN 5 interferon; TCR 5 T cell
receptor; TNF 5 tumor necrosis factor.
Inflammatory response of sarcoidosis
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