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This is Sarcoidosis

Sarcoidosis is a systemic inflammatory disease of unknown etiology. The disease is primarily characterized by the formation of non-caseating granulomas in affected organs.

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Despite advances in diagnosis and management, substantial research gaps remain in understanding the disease's etiology and pathogenesis and developing optimal treatment strategies. Addressing these gaps is crucial for improving patient outcomes and advancing the overall understanding of sarcoidosis.

From the genetic standpoint, sarcoidosis is a multifactorial and polygenic disease resulting from complex interactions between genetic predispositions and environmental factors. These interactions are likely to contribute to the diverse clinical manifestations and outcomes observed in sarcoidosis patients. Sarcoidosis is an umbrella of many clinical phenotypes, each with a specific genetic architecture but with some shared immune-related genes, such as those in the major histocompatibility complex (MHC) region. The MHC region encompasses the human leukocyte antigen (HLA) sub-region. The MHC region is located on chromosome 6 in the human genome. 


Epidemiological studies have shown that sarcoidosis is widespread worldwide. However, in some populations, it may be rare. The prevalence of the disease ranges from 0.2 per 100,000 in South America to 160 per 100,000 in Sweden. Sarcoidosis occurs equally in men and women and typically manifests in the third decade of life. Geography, ancestry, and ethnicity strongly influence the disease's presentation, prevalence, and incidence of the disease.
Sarcoidosis significantly impacts the lives of individuals attending specialized clinics, resulting in substantial direct and indirect healthcare costs and placing financial strain on patients.

Sarcoidosis is usually characterized by two clinical phenotypes: Löfgren's syndrome (LS)  and non-Löfgren's syndrome (nonLS). Löfgren's syndrome (LS) is an acute form of the disease that resolves independently over 2-5 years, particularly in patients who carry the HLA-DRB1*03 allele. However, LS is a rare phenotype in many populations except in Sweden and some populations of European ancestry. In Sweden, the LS group accounts for 30% of the sarcoidosis population. The remaining patients have a non-resolving disease, which is typically referred to as non-Löfgren syndrome (nonLS) or simply sarcoidosis. In this group, the disease progresses over the years, potentially affecting multiple organs such as the heart, kidneys, eyes, skin, nervous system, musculoskeletal system, reproductive system, lymph nodes, liver, and spleen, and sometimes developing into extensive fibrosis, which occurs in about 25% of patients.

Impact of sarcoidosis

Sarcoidosis patients often experience significant challenges such as fatigue, depression, cognitive issues, and pain syndromes. These issues can significantly affect their quality of life, leading to prolonged sick leave and even unemployment. The specific molecular mechanisms connecting sarcoidosis to these conditions are not fully understood. 

Significant gaps exist in our current understanding of the clinical outcomes of sarcoidosis and its comorbidities. We aim to find genetic factors (a.k.a. biomarkers) that can predict clinical outcomes and determine the genetic factors and molecular processes contributing to the development of other diseases that coexist with sarcoidosis.

The mortality rate from sarcoidosis, particularly in patients with the nonLS phenotype, is about five percent. Deaths are often attributed to progressive lung scarring (pulmonary fibrosis) complicated by bleeding from the lung vessels, leading to respiratory failure, or the development of granulomas in the heart, causing abnormal heart rhythms and resulting in right ventricular failure.

Genetic determinants in sarcoidosis

Our team and others have shown that genetics plays a significant role in disease pathogenesis. From our research work, we showed that the genetics of sarcoidosis phenotypes, Löfgren's syndrome (LS) [the acute form of sarcoidosis] and non-Löfgren's syndrome (nonLS) [the progressive form of the disease], have distinct genetic architectures. These clinical phenotypes have common genes, such as those located in the HLA class II region on chromosome 6 and elsewhere in the genome, suggesting a distinct genetic architecture for a particular phenotype. 

We also identified the same pattern in the genetics of disease chronicity among the LS and nonLS groups. Moreover, we showed that the expression of immune cells in the lungs and blood also has different expression patterns among the LS and nonLS groups. Thus, from these studies, we can deduce that sarcoidosis is an umbrella of many phenotypes that have their specific genetic architecture (i.e., endophenotypes or endotypes).

Sarcoidosis  LS and nonLS are multifactorial disease entities likely to result from the interplay between multiple genes and environmental factors, each exerting only a modest effect on the overall risk. The distinctive genetic arrangements in each phenotype possess essential functions that contribute to the disease diversity observed in the clinical presentation and course of the disease.

Sarcoidosis and autoimmunity

Sarcoidosis is defined by the development of granulomas in the affected organ, consisting of epithelioid cells, CD4 lymphocytes, mature macrophages, multinucleated giant cells, CD8 lymphocytes, and antigen-presenting cells (APCs). This immune system imbalance is orchestrated by various cellular processes triggered by an as-yet-unknown cause.
Interestingly, although sarcoidosis is not categorized as an autoimmune disease, its pathology shares molecular mechanisms found in autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, scleroderma, sjögren's syndrome, and multiple sclerosis, to name a few.

Research studies, including our own, have shown that the molecular mechanisms underlying sarcoidosis highlight an adaptive-mediated immune response influenced by specific genetic architectures unique to each clinical phenotype. We have observed differences in gene associations, gene expression patterns, and regulatory elements that uniquely characterize the genetic landscape of sarcoidosis phenotypes. Further research is necessary to identify the molecular mechanisms and signaling pathways driving the adaptive-mediated immune response in sarcoidosis.