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Here is a great article and one that I've cited a few times lately.

In This Article

References

The Etiologic Agent of Sarcoidosis

from CHEST

Posted 07/25/2003

Marc A. Judson, MD, FCCP

Yesterday I evaluated a new patient with sarcoidosis who asked whether the

disease was caused by her work as a short-order cook. The week previously, a

patient wondered whether his work in a textile mill caused his sarcoidosis,

while another was convinced that her sarcoidosis resulted from furniture polish

fumes. In the past, I would have given my standard answer to such queries:

although we do not know what causes sarcoidosis, there is no evidence suggesting

an excessive number of cases in short-order cooks, textile workers, and those

exposed to furniture polish. In short, these patients' exposures had been

unlikely culprits in the development of their disease.

This is no longer my answer to my patients' questions, and the provocative

article by Reich in this issue of CHEST (see page 367) explains the reason for

abandoning it. There is mounting evidence suggesting that the " cause " of

sarcoidosis does not relate to a specific exposure but rather to an abnormal

host immunologic response to one of several exposures.

A necessary interplay between specific combinations of exposures and host

responses in the pathogenesis of sarcoidosis would explain why so many studies

have come to conflicting conclusions regarding the etiology of the disease. For

example, two studies[1,2] using polymerase chain reaction techniques have

detected mycobacterial DNA in the lung tissue of 44% and 50%, respectively, of

sarcoidosis patients, while other studies[3-6] have established that

mycobacterial DNA was rare or absent in sarcoidosis. As stated by Reich, one

study linked sarcoidosis to human-made mineral fibers,[7] whereas another large

study of human-made mineral fiber workers found no such association.[8] Although

some studies have shown a higher prevalence of Propionibacterium acnes and

Chlamydia species in the lungs of sarcoidosis patients than in control

subjects,[9,10] these findings have not been universal.[11,12]

Our current understanding is that the development of sarcoidosis requires at

least the three following major events: exposure to an antigen; acquired

cellular immunity directed against the antigen mediated through

antigen-presenting cells and antigen-specific T-lymphocytes; and the appearance

of immune effector cells that promote a non-specific inflammatory response.[13]

More specifically, alveolar macrophages from patients with pulmonary sarcoidosis

show enhanced antigen-presenting capacity by the enhanced expression of human

leukocyte antigen (HLA; major histocompatibility complex)-class II molecules,

which is probably induced by an interaction with the sarcoidosis antigen and

possibly interferon (INF)-.[14] These macrophages recognize, process, and

present the putative antigen to CD4 + T cells of the T helper (Th)-1 type.[14]

These activated macrophages produce IL-12, which induces a lymphocyte shift

toward a Th-1 profile and causes T lymphocytes to

secrete INF-. These activated T cells release IL-2 and chemotactic factors that

recruit monocytes and macrophages to the site of disease activity.[14] IL-2 is

also activated and expands various T-cell clones.[15] INF- is able to further

activate macrophages and to transform them into giant cells, which are important

building blocks of the granuloma.[14,16]

Therefore, the evidence suggests that the immunologic process that leads to

sarcoidosis begins when an antigen is presented by a macrophage via HLA class II

molecules to a T lymphocyte. This induces a Th-1 T-lymphocyte response whereby

cytokines are released that result in granuloma formation. Scandinavian

investigators[17] have demonstrated a strong association of a specific class of

lung T cells bearing V2.3 T-cell-antigen receptors in patients with clinically

active acute sarcoidosis. These patients express HLA-DR3, DQ2. These results

suggest that a single antigen paired with a single antigen-presenting molecule

may trigger the immunologic response that results in this sarcoidosis

phenotype.[13] However, many other sarcoidosis patients have more than one

T-cell clone or no increase in oligoclonal T cells.[13] In addition, different

sarcoidosis phenotypes are associated with different HLA class II molecules.[18]

These data support the concept that

there are multiple sarcoidosis antigens or epitopes recognized by different

T-cell clones that are paired with different HLA class II molecules.[13]

Reich further speculates that the granulomatous response of sarcoidosis

represents an " immunologic fallback position " in persons who are unable to clear

the immunologic agents in a more efficient manner. The data to support this

conjecture are minimal. Reich's foundation for this concept consists of one

abstract[19] that examined the intradermal injection of Kveim reagent. In that

study, healthy subjects demonstrated features of delayed hypersensitivity,

including infiltrates of Th and suppressor cells with markers of activation (eg,

Tac+ and Leu9+) and dendritic Langerhans cells (eg, OKT6 and RFD+) with strong

HLA-DR expression 11 and 18 days after intradermal injection. In contrast,

Kveim-positive sarcoidosis patients failed to develop this response. These

findings suggest that the granulomas of sarcoidosis may be the result of a

sluggish delayed hypersensitivity response, which subserves the antigen,

allowing it to remain undetected or to be

inadequately cleared from tissue.

Although a paucity of investigational data supports the model of ineffective

clearance of putative sarcoid antigens by the sarcoid granuloma, Reich cites an

abundance of clinical evidence. This concept would explain why corticosteroids

might promote the relapse of sarcoidosis[20-22] by possibly further inhibiting

the already sluggish granulomatous response. It would also explain why patients

who have a brisk immunologic response, such as those with erythema nodosum, have

a good prognosis. And, it would explain why individuals with combined variable

immunodeficiency, many of whom have an associated deficiency in T lymphocytes,

have a high rate of developing sarcoidosis.[23]

However, the concept that sarcoidosis granulomas are inefficient at clearing

antigens does not explain all the clinical aspects of the disease. For instance,

it does not explain the sarcoidosis-like reaction that can occur when highly

active antiretroviral therapy is given to HIV-infected patients.[24] It is

likely that the antigens that cause sarcoidosis are present in the HIV-infected

individual who has a low CD4+ count. However, the CD4+ lymphocyte number and

function is inadequate to mount a significant Th-1-induced granulomatous

response until highly active antiretroviral therapy is administered.[25]

Therefore, in this example, sarcoidosis develops in a better constituted immune

system, not in a more defective one. Inefficient clearance by sarcoid granulomas

also would not explain the development of sarcoidosis in allografts following

transplantation,[26] as supposedly these transplanted organs would be free of

the antigen in the excised tissues

that caused the granulomatous response. Possibly, granulomas are formed in this

instance by the immunologic response cross-reacting with allograft tissue

instead of an antigen.

Regardless of the answers to these concerns, it is sobering to consider Reich's

argument that there is not any one single agent and that there is not one

discrete immunologic defect that causes sarcoidosis. For sarcoidosis to occur,

patients may have to experience a specific interaction between one or several

exposures and one or several abnormal immunologic responses. If this model is

correct, it will be extremely difficult to prove. And perhaps the absence of

proof for any etiology of sarcoidosis may be the most compelling argument

supporting Reich's hypothesis. We still have not figured out the cause of

sarcoidosis perhaps because there is not just one cause.

Reprint Address

Reproduction of this article is prohibited without written permission from the

American College of Chest Physicians (e-mail: permissions@...).

Correspondence to: Marc A. Judson, MD, FCCP, Department of Medicine: Pulmonary,

96 Lucas St, PO Box 250623, ton, SC 29425

Dr. Judson is affiliated with the Medical University of South Carolina,

Department of Pulmonary and Critical Care.

CHEST 124(1):6-8, 2003. © 2003 American College of Chest Physicians

Discussions

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Guest guest

Here is a great article and one that I've cited a few times lately.

In This Article

References

The Etiologic Agent of Sarcoidosis

from CHEST

Posted 07/25/2003

Marc A. Judson, MD, FCCP

Yesterday I evaluated a new patient with sarcoidosis who asked whether the

disease was caused by her work as a short-order cook. The week previously, a

patient wondered whether his work in a textile mill caused his sarcoidosis,

while another was convinced that her sarcoidosis resulted from furniture polish

fumes. In the past, I would have given my standard answer to such queries:

although we do not know what causes sarcoidosis, there is no evidence suggesting

an excessive number of cases in short-order cooks, textile workers, and those

exposed to furniture polish. In short, these patients' exposures had been

unlikely culprits in the development of their disease.

This is no longer my answer to my patients' questions, and the provocative

article by Reich in this issue of CHEST (see page 367) explains the reason for

abandoning it. There is mounting evidence suggesting that the " cause " of

sarcoidosis does not relate to a specific exposure but rather to an abnormal

host immunologic response to one of several exposures.

A necessary interplay between specific combinations of exposures and host

responses in the pathogenesis of sarcoidosis would explain why so many studies

have come to conflicting conclusions regarding the etiology of the disease. For

example, two studies[1,2] using polymerase chain reaction techniques have

detected mycobacterial DNA in the lung tissue of 44% and 50%, respectively, of

sarcoidosis patients, while other studies[3-6] have established that

mycobacterial DNA was rare or absent in sarcoidosis. As stated by Reich, one

study linked sarcoidosis to human-made mineral fibers,[7] whereas another large

study of human-made mineral fiber workers found no such association.[8] Although

some studies have shown a higher prevalence of Propionibacterium acnes and

Chlamydia species in the lungs of sarcoidosis patients than in control

subjects,[9,10] these findings have not been universal.[11,12]

Our current understanding is that the development of sarcoidosis requires at

least the three following major events: exposure to an antigen; acquired

cellular immunity directed against the antigen mediated through

antigen-presenting cells and antigen-specific T-lymphocytes; and the appearance

of immune effector cells that promote a non-specific inflammatory response.[13]

More specifically, alveolar macrophages from patients with pulmonary sarcoidosis

show enhanced antigen-presenting capacity by the enhanced expression of human

leukocyte antigen (HLA; major histocompatibility complex)-class II molecules,

which is probably induced by an interaction with the sarcoidosis antigen and

possibly interferon (INF)-.[14] These macrophages recognize, process, and

present the putative antigen to CD4 + T cells of the T helper (Th)-1 type.[14]

These activated macrophages produce IL-12, which induces a lymphocyte shift

toward a Th-1 profile and causes T lymphocytes to

secrete INF-. These activated T cells release IL-2 and chemotactic factors that

recruit monocytes and macrophages to the site of disease activity.[14] IL-2 is

also activated and expands various T-cell clones.[15] INF- is able to further

activate macrophages and to transform them into giant cells, which are important

building blocks of the granuloma.[14,16]

Therefore, the evidence suggests that the immunologic process that leads to

sarcoidosis begins when an antigen is presented by a macrophage via HLA class II

molecules to a T lymphocyte. This induces a Th-1 T-lymphocyte response whereby

cytokines are released that result in granuloma formation. Scandinavian

investigators[17] have demonstrated a strong association of a specific class of

lung T cells bearing V2.3 T-cell-antigen receptors in patients with clinically

active acute sarcoidosis. These patients express HLA-DR3, DQ2. These results

suggest that a single antigen paired with a single antigen-presenting molecule

may trigger the immunologic response that results in this sarcoidosis

phenotype.[13] However, many other sarcoidosis patients have more than one

T-cell clone or no increase in oligoclonal T cells.[13] In addition, different

sarcoidosis phenotypes are associated with different HLA class II molecules.[18]

These data support the concept that

there are multiple sarcoidosis antigens or epitopes recognized by different

T-cell clones that are paired with different HLA class II molecules.[13]

Reich further speculates that the granulomatous response of sarcoidosis

represents an " immunologic fallback position " in persons who are unable to clear

the immunologic agents in a more efficient manner. The data to support this

conjecture are minimal. Reich's foundation for this concept consists of one

abstract[19] that examined the intradermal injection of Kveim reagent. In that

study, healthy subjects demonstrated features of delayed hypersensitivity,

including infiltrates of Th and suppressor cells with markers of activation (eg,

Tac+ and Leu9+) and dendritic Langerhans cells (eg, OKT6 and RFD+) with strong

HLA-DR expression 11 and 18 days after intradermal injection. In contrast,

Kveim-positive sarcoidosis patients failed to develop this response. These

findings suggest that the granulomas of sarcoidosis may be the result of a

sluggish delayed hypersensitivity response, which subserves the antigen,

allowing it to remain undetected or to be

inadequately cleared from tissue.

Although a paucity of investigational data supports the model of ineffective

clearance of putative sarcoid antigens by the sarcoid granuloma, Reich cites an

abundance of clinical evidence. This concept would explain why corticosteroids

might promote the relapse of sarcoidosis[20-22] by possibly further inhibiting

the already sluggish granulomatous response. It would also explain why patients

who have a brisk immunologic response, such as those with erythema nodosum, have

a good prognosis. And, it would explain why individuals with combined variable

immunodeficiency, many of whom have an associated deficiency in T lymphocytes,

have a high rate of developing sarcoidosis.[23]

However, the concept that sarcoidosis granulomas are inefficient at clearing

antigens does not explain all the clinical aspects of the disease. For instance,

it does not explain the sarcoidosis-like reaction that can occur when highly

active antiretroviral therapy is given to HIV-infected patients.[24] It is

likely that the antigens that cause sarcoidosis are present in the HIV-infected

individual who has a low CD4+ count. However, the CD4+ lymphocyte number and

function is inadequate to mount a significant Th-1-induced granulomatous

response until highly active antiretroviral therapy is administered.[25]

Therefore, in this example, sarcoidosis develops in a better constituted immune

system, not in a more defective one. Inefficient clearance by sarcoid granulomas

also would not explain the development of sarcoidosis in allografts following

transplantation,[26] as supposedly these transplanted organs would be free of

the antigen in the excised tissues

that caused the granulomatous response. Possibly, granulomas are formed in this

instance by the immunologic response cross-reacting with allograft tissue

instead of an antigen.

Regardless of the answers to these concerns, it is sobering to consider Reich's

argument that there is not any one single agent and that there is not one

discrete immunologic defect that causes sarcoidosis. For sarcoidosis to occur,

patients may have to experience a specific interaction between one or several

exposures and one or several abnormal immunologic responses. If this model is

correct, it will be extremely difficult to prove. And perhaps the absence of

proof for any etiology of sarcoidosis may be the most compelling argument

supporting Reich's hypothesis. We still have not figured out the cause of

sarcoidosis perhaps because there is not just one cause.

Reprint Address

Reproduction of this article is prohibited without written permission from the

American College of Chest Physicians (e-mail: permissions@...).

Correspondence to: Marc A. Judson, MD, FCCP, Department of Medicine: Pulmonary,

96 Lucas St, PO Box 250623, ton, SC 29425

Dr. Judson is affiliated with the Medical University of South Carolina,

Department of Pulmonary and Critical Care.

CHEST 124(1):6-8, 2003. © 2003 American College of Chest Physicians

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