Sarcoidosis is a multisystemic inflammatory disease characterized by noncaseating granulomas, consisting of CD4⁺ T cells and macrophages surrounded by CD8⁺ T cells (1). It frequently affects lungs and lymph nodes but may involve any organ (2). Aberrant interactions of T cells, monocytes, and macrophages after exposure to triggering factors, e.g., (in)organic particles or antigens from infectious agents may contribute to the pathogenic process (2, 3). Genetic susceptibility for sarcoidosis was found associated with distinct human leukocyte antigen (HLA) types, as detected by genome-wide association studies (4, 5). In particular, genetic variants in HLA-DRB1 located in the MHC class II region and the HLA class I antigens A1 and B8 have been associated with an increased risk of disease (6–8).

While DRB1 alleles, such as *03:01 and *03:02, can confer protection against chronic disease (8, 9), HLA DRB1*14 and DRB1*15 are associated with chronic sarcoidosis (2). HLA types implicated in the development of sarcoidosis depending on ethnicity are, among others, HLA-B51 (10), DQB1*02:01 (11), DRB1*03:01 (12, 13), DRB1 *11:01 (13, 14), and DRB1*15:01 (12, 14). An association between sarcoidosis and hematologic malignancies has been observed, documenting sarcoidosis occurring before, during, or after the diagnosis of lymphoma (15–17). Sarcoidosis in the context of hematopoietic stem cell transplantation (HSCT) has been reported rarely (18).

In this study, we determined the incidence and characteristics of sarcoidosis following allogeneic (allo) and autologous (auto) HSCT in a cohort of consecutive patients in the context of findings with previously reported patient data, aiming at a comprehensive clinicopathological view at this rare condition.

Of a total number of 2,022 patients who underwent HSCT from 2001 to 2021 at our center, 4 patients who developed sarcoidosis after HSCT were analyzed. An additional 15 patients identified in the literature were included for further analysis. The patient flow is depicted in Figure 1.

Symptomatic sarcoidosis after HSCT represents a rare condition, and we here provide an estimate of incidences in the autologous and allogeneic transplantation setting and its clinical characteristics. Sarcoidosis post HSCT occurred in patients receiving both allogeneic and autologous stem cell transplantations at a ratio of 3:1, both in the UMG and the previously published patients. The increased frequency of sarcoidosis after allogeneic transplantation is compatible with the strong activation of the immune system upon engraftment in these patients. This observation suggests that a preformed immunological reaction may occur with increasing immunological competence of the Tcell repertoire and/or antigen-presenting cells (APCs). This notion is further supported by the HLA allele associations observed for sarcoidosis post HSCT, which reiterates the associations described for sporadic sarcoidosis (2, 8–14) (Table 1). While the antigen(s) triggering sarcoidosis remain elusive, our observations were best compatible with a minor self-antigen or a preexisting viral antigen, which is presented to the newly engrafted immune system in an HLA allele associated efficacy to elicit the sarcoidosis-type reaction in the post transplantation period (median time of 17 months, 20 months after allo HSCT, and 7 months after auto HSCT).

Seven of 13 patients with sarcoidosis post allogeneic HSCT also developed acute or chronic GvHD in the post-transplantation follow-up. Dependent on the precise transplantation setting, approximately 60% of patients develop GvHD after allo HSCT. Thus, our data do not support an association of sarcoidosis and GvHD, albeit this is limited by the small patient numbers.

Immunologically, granuloma formation is initiated by an interaction between CD4+ T cells and APCs, such as macrophages or dendritic cells via HLA class II antigen–peptide complex leading to T-cell activation, differentiation into Th1 cells, secretion of interleukin (IL)-2 and interferon (IFN)-g, and augmented macrophage tumor necrosis factor (TNF)-a production, resulting in immune response amplification (31–33). After granuloma formation, there are two possible outcomes: Granuloma formation can either resolve, if the peptide antigens are presented by HLA-DR3 molecules on dendritic cells or macrophages and subsequently recognized by T cells leading to the release of a range of cytokines, or persistent granulomatous inflammation with subsequent tissue damage requiring immunosuppressive therapy (32). The latter is thought to occur if the antigen recognition is inefficient and can be due to peptides displayed by molecules other than HLA-DRB1*03 (HLA-DR3) or T cells that are not capable of generating efficient T-cell clones (34).

Two agents that interfere with both Tcell and- dendritic cell (DC)-mediated immunity, which is necessary for the resolution of sarcoid granulomas, are ATG and ALM. Two of our allo HSCT patients received ATG, while it was not reported in any of the case reports. ATG, a polyclonal antibody, is used to prevent GvHD and suppress allograft rejection. Owing to its polyclonality, there are diverse effects of ATG on the immune system, among them Tcell depletion, modulation of leukocyte/endothelial interactions, apoptosis in B cells, interference with DC function and the induction of regulatory T and natural killer (NK) T cells (35). So far there have been no reported cases linking sarcoidosis to ATG treatment.

Alemtuzumab, however, has been associated with the development of sarcoidosis and there are several case reports describing the occurrence of sarcoidosis post ALM treatment in multiple sclerosis patients (36–38). While the exact mechanism by which ALM triggers sarcoidosis is not yet known, a dysregulation in the Th1/Tc1 cell/IFN-γ network and the development of autoantibodies by dysregulated B cells has been postulated (39). The immune dysregulatory effects of ATG and ALM could play a role in the development of sarcoidosis in the post HSCT setting; however, taking into account the heterogenous usage of ATG and ALM in the reported patients, no clear causal link can be inferred.

Different hypotheses have been proposed, aiming to explain the pathogenesis of sarcoidosis after malignancy: Firstly, it has been postulated that sarcoidosis develops as a reaction to the immunosuppressive effect of chemotherapies or to a specific chemotherapy agent, such as bleomycin, known to achieve high concentrations in LN, skin, and lung tissue (40).

Secondly, Brincker et al. hypothesized that the appearance of sarcoidosis post malignancy may be driven by antigens derived from tumor cells leading to immunological events resulting in granuloma formation (41). Thirdly, Kornacker et al. suggested that underlying immunologic disturbances associated with the primary malignancy may lead to the formation of epithelioid granulomas (42).

In three patients the occurrence of sarcoidosis has been reported after possible transmission from the donor (23–25). The data from our patient cohort do not support an increased risk of transmission, as none of our patients was transplanted from a donor with a previous history of sarcoidosis, and vice versa, none of the patients with sarcoidosis in their pre-transplant medical history experienced sarcoidosis recurrence.

The immunological environment post HSCT, similar to that present in sarcoidosis pathogenesis outside of the context of HSCT, could promote the development of sarcoidosis, especially in a genetically susceptible individual with a specific HLA allele. The reported disease pathogenesis and potentially triggering factors are summarized in Figure 5: Before HSCT, the conditioning regimen as well as underlying disease damage of host tissues induce pro-inflammatory cytokines such as TNF-a, chemokines, and costimulatory molecules on host APCs. Following HSCT, donor T cells proliferate and differentiate in response to activated host APCs, then expressing IFN-g, IL-2, and TNF-a, leading to T-cell expansion and differentiation into Th1 vs. Th2 subtypes (43, 44). This is followed by an increase in the number of suppressor/cytotoxic lymphocytes and then of helper–inducer phenotype T cells, thereby inverting CD4+/CD8+ ratios. A normalization of CD4+/CD8+ T cell ratios takes place approximately 1 to 2 years after HSCT (45, 46) with a longer time span in older patients, whose thymic function is less pronounced.

During immune reconstitution, higher levels of cytokines such as MCP-1, CCR1, CCR2, IL-8, and Rantes are present, leading to a tissue environment promoting the formation of non-necrotizing epithelioid granulomas (47–49).

All allogenously transplanted patients reported previously, including those in our cohort, developed sarcoidosis after complete donor engraftment of their bone marrow, suggesting that the development of sarcoidosis in these circumstances was initiated by the donor immune system. Interestingly, it has been shown that individuals with a HLA-B8/DR3 phenotype produce higher amounts of TNF-a compared to their IFN-g generation potential (50), making them susceptible to humoral hyperreactivity and anergy under an environmental stress. Overall, the time course of sarcoidosis development in the described patients within this report (ranging from three to 120 months after HSCT) is consistent with what would be expected from the current hypothesized mechanisms of granuloma formation, which usually take months rather days or weeks to form (51).

The older age and shorter time to the onset of sarcoidosis post HSCT of the analyzed patients compared to the normal population might be explained with the progressive involution of thymic tissue during aging with a decline in T-cell output and T-cell senescence with restricted T-cell receptor repertoire diversity, leading to a slower immune reconstitution and impaired immune responses following transplantation (46). However, a bias that patients with malignancies, especially lymphomas, are generally older must be considered.

The occurrence of extrapulmonary manifestations of sarcoidosis in patients with leukemia, MDS, and MF compared to lymphoma patients has been linked to malignant antigens as a sarcoidosis trigger in leukemic diseases (41). While the remission status prior to HSCT of most reported patients in the literature is unknown, sarcoidosis in our cohort patients occurred exclusively in patients with complete disease remissions, rendering a malignant antigenic trigger for sarcoidosis unlikely. Specific chemotherapeutic agents, such as bleomycin, have been hypothesized to trigger sarcoidosis. Interestingly, the majority of the allo HSCT patients received a regimen including BU, FLU, and CYC. There have been no reports implicating FLU and BU in the formation of sarcoidosis, CYC has been used previously in the treatment of severe cardiac or neurosarcoidosis (52). TBI is known to lead to a delayed immune reconstitution (46).

Our study has several limitations. First, sarcoidosis post HSCT is a rarely reported event, although based on observations by Bhagat et al. (18) and the prevalence in our cohort of HSCT patients, the occurrence in HSCT might be higher than previously estimated. Also, the number of patients with accesible data for analysis was limited and the small number of cases may influence trends we observed in sub-groups during data analysis. Furthermore, multicentric analyses in additional cohorts may gain more granular insights into the prevalence, potential triggers, and the pathogenesis of sarcoidosis post HSCT. Lastly, it has to be noted that the diagnosis of sarcoidosis can never be ascertained based on granulomas alone, but, at least in our patients, we are confident to have excluded alternative reasons for granulomatous reaction. For the patients in the literature, we had to rely on the reported data. Nevertheless, our report has several strengths: To our knowledge, this report represents the most comprehensive analysis from a single center in conjunction with previously published data. The strong HLA association reported and corroborated by our data suggest that sarcoidosis occurrence in this vulnerable population is influenced by a genetic predisposition requiring additional immunological events in the context of HSCT.

Based on the 2022 HSCT patients that have been treated at our institution over a 20-year span and four cases of sarcoidosis occurring therein, we estimate the incidence at 156 and 58 cases per 100,000 for allo and auto HSCT, respectively, which is higher than reported by Bhagat et al. (18) and higher than reported in the general German population (53). Based on the low number of incident cases, this is, however, only a rough estimate. Overall, sarcoidosis after allo or auto HSCT is a rare event, frequently affects the lungs and skin, but usually responds to GC treatment. Further insights into the interplay between T cell reconstitution and the formation of sarcoidosis may also provide insight into the overall pathogenesis of sarcoidosis.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the University Medical Center Göttingen (protocol number 30/6/21). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

RW-K and PK designed the study. Material preparation, data collection, and analysis were performed by RW-K, JB, JK, JGR, GW, and PK. JH and WJ treated patients and edited the manuscript. The figures were created by RW-K and PK. The first draft of the manuscript was written by RW-K. All authors contributed to the article and approved the submitted version.

We acknowledge support by the Open Access Publication Funds of the Göttingen University.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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