Infection with T. whipplei results in atypical activation of bone marrow-derived macrophages (BMDMs) with M2 polarization which associated with Th2 response and type I interferon (IFN) response (31). The impaired T. whipplei-specific Th1 reactivity also plays an important pathogenetic role (32, 33). The combined effect of the above cause persistent immunological unresponsiveness and cytokine-induced activation of regulatory cells (Tregs) which may be attributed to a peculiar genetic polymorphism in cytokine genes (34).

Macrophage polarization is a dynamic process through which macrophages acquire specific features, including M1 and M2 polarization (35). T. whipplei-stimulated macrophages and duodenal tissues acquire phenotypes of M2/alternatively activated macrophages (36) which are linked to the persistence of bacterial pathogens in tissues and the chronic evolution of infectious diseases (37). Live T. whipplei also induces a strong type I IFN response, which is essential for bacterial pathogenicity, and induces c-Jun N-terminal kinase (JNK) phosphorylation to promote macrophage apoptosis. The JNK-independent intracellular replication of T. whipplei (compatible with M2) is also associated with type I IFN response (31). The crosstalk between type I and type II IFNs affects the host susceptibility to bacterial infection, and α/β IFNs downregulate the expression of IFN-γ receptors (38). As the production of IFN-γ and interleukin-12 (IL-12) is closely related (3), the reduction in IFN-γ may also result from reduced IL-12 production from antigen-presenting cells, which reveal an immature myeloid dendritic cell (M-DC) phenotype, supporting the systemic distribution of T. whipplei and perpetuating chronic infection (39) in all relevant tissues. As a result, marked reduction in the local inflammatory response has been reported (40).

The reduced T. whipplei-specific Th1 response in patients with WD (32) also leads to reduced production of IFN-γ in both peripheral blood and the lamina propria of the duodenum (36). Imperceptive IFN-γ production is thought to be critical in the pathophysiology of WD (33). In addition to inducing T. whipplei clearance by upregulating the small GTPase activity required for phagosome conversion and inducing the formation of phagosomes into phagolysosomes, IFN-γ also suppresses the production of IL-16, which inhibits the fusion of T. whipplei phagosomes with lysosomes. This is achieved by regulating the protein level of cathepsin D in macrophages and upregulating the expression of auto- and pro-apoptotic genes and immunomodulatory genes, such as IL-10 and transforming growth factor (TGF-β) (41). In the presence of TGF-β, precursor CD4+ T-cells differentiate towards regulatory cells (Tregs) characterized by the expression of foxhead box P3+ (FOXP3+) which express specific anti-inflammatory cytokines such as IL-10 and TGF-β (42). This is consistent with the immunopathological observations in WD. Patients with CWD have higher peripheral blood Tregs activation and increased duodenal IL-10 and TGF-β secretion (43). IL-16 also induces the recruitment and differentiation of CD4-expressing cells into tolerogenic cells (3). This contribution to local immune tolerance is also enhanced by a membrane or soluble HLA-G by inhibiting TNF expression (18).

The more frequently discussed questions about the pathogenesis of IRIS focus on the degree of immunosuppression resulting from the combined effects of the underlying antigenic burden and patient drug history. IRIS is ascribed to the activation of a non-specific Th1 response underlying the lower CD4+ T cell baseline coupled with reconstituted Treg inadequacy (44). The above characteristics can lead to barrier dysfunction, which can be the cause of prolonged microbial translocation (MT). The resulting entry of endotoxin into the bloodstream can lead to immune reconstitution disorders with systemic immune activation in IRIS CWD (5).

In summary, WD induces a combined effect in which the immune system is suppressed, leading to a high antigen load in affected local tissues. Furthermore, up to 50% patients with classic Whipple’s disease are initially misdiagnosed and treated with immunosuppressive drugs, such as disease-modifying antirheumatic drugs (DMARDs), anti-necrosis factor alpha, glucocorticoids, or drugs, with potentially fatal consequences (16). When treatment with these drugs is discontinued, inflammatory signs may rebound (4), and the degree of CD4+ T cells in the peripheral blood reduction increases with the time of immunosuppressant application (44).

Tumor necrosis factor inhibitors (TNFIs) may reduce phagolysosome fusion, resulting in increased intracellular replication and macrophage apoptosis (45, 46). Susceptibility to IRIS depends primarily on the absence of TNF-signaling (47). Moreover, antimicrobials per se can act as proinflammatory stimulants or upregulate Th1 responses (48). It has been shown that IFN-γ production by CD4+ T cells in response to staphylococcal enterotoxin B (SEB) increases significantly in patients with WD developing IRIS during antibiotic treatment but remains low in treated patients without IRIS (44). Antibiotics not only induce dysfunction of the intestinal epithelial tight junction (TJ) barrier but are also associated with dysbiosis of the intestinal microbiota (49).

Crossing of the defective mucosal barrier by gut microbiota was also demonstrated in a study evaluating pathological damage to the small intestinal mucosa in patients with CWD. The study revealed that elevated levels of lipopolysaccharide-binding protein (LBP), lipopolysaccharide (LPS), and sCD14, definitive alternative markers of increased intestinal permeability and MT, provide direct and indirect evidence of this invasion (50). The link between barrier defects in the intestinal mucosa and systemic immune activation in patients with WD developing IRIS has been further investigated and characterized as a storm in TNF-a expression (25), with TNF-a triggering the NF-κB signaling pathway. This pathway is also an index of inflammation and is synergized by the expression of MLCK activated by IFN-γ, an event that is necessary to promote redistribution of tight junction proteins and paracellular permeability (51). However, the disruption of TJs often leads to increased intestinal permeability, a pathological state termed “leaky gut syndrome” (LGS) (52). The leaky intestinal barrier enhances microbial translocation, which can be predicted by markers as described above.

Moreover, very recent studies have shown that endotoxaemic episode could be a potential mediator of dysbalanced T cell reconstitution (5). The diverse reservoir of LPS is the gut microbiota, on which LPS depends as a stimulator of the host immune response and as a promoter of pro-inflammatory cytokine secretion (53). The pathologic mechanism leads to an imbalance in T-cell recruitment and inflammatory activation in CWD IRIS, with a positive correlation with sCD14 levels and a negative correlation with the antibody (EndoCAb) titre (5). Therefore, monitoring of inflammatory and microbial translocation markers in patients with WD may be helpful to identify patients who are at risk of developing IRIS and preventing misdiagnosis of treatment failure due to the recurrence of inflammation. However, this intervention needs to be investigated in future studies. Figure 1 compares the brief process of CWD with CWD IRIS.

Fever is described as a sudden inflammatory response in IRIS in non-HIV patients and can also be caused by an infectious agent (54). Fever is also a typical symptom of WD. Fever that resolves after 48 hours and does not recur is not considered to be IRIS in 80%-86.7% of cases (4, 22). The administration of oral corticosteroids for fever generally shows a response within 24 hours (4).

The incidence of arthritis is high, ranging from almost 93.3% to 100% (4, 22). The investigation of WD-associated arthropathy has been the focus of considerable research. In 1907, Whipple, the pathologist who first described the disease now bearing his name, noted the characteristics of joint involvement which was a part of the clinical manifestations of the first patient with the condition. In 2013, Krol and de Meijer entitled their letter to the editor “Palindromic rheumatism: consider Whipple’s disease.” (27) In 2021, logistic regression analysis was conducted to distinguish WD disease from rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, and palindromic arthritis (55). Despite the fact that joint involvement is a general manifestation of WD IRIS, there has been limited research on this subject with some reports in the literature describing the condition as “recurrent arthritis.” (4).

Orbitopathy refers to an inflammatory orbital disease with symptoms, including orbital pain, pseudotumors of the eye socket, proptosis, diplopia, and vision loss after hormonal treatment, accounting for 26.7% (4). Unilateral and bilateral orbitopathy has also been reported but is very rare, and biopsy of the superior and lateral rectus extraocular muscles showed CD68-positive macrophages and occasional CD3-positive T cells between the muscle fibers (30). The observed ocular impairment in WD highlights the fact that antibiotics and steroids therapy should not be administered alone but in combination with other measures, such as ocular decompression to prevent ocular damage (56).

Skin disease occurred after WD treatment in 13.3% of cases (4). Subcutaneous erythematous nodules are the main cutaneous manifestations of IRIS in the treatment of WD; these are rare and are most commonly found on the lower limbs, but can also be found on the trunk and wrists (26, 57, 58). Inflammatory reactive dermatoses, which can occur at all stages of WD, including erythema nodosum (EN)-like lesions after antibiotic treatment, are distinct from dystrophic dermatoses, which can be improved with antibiotic treatment but occur only in the late stages of WD. EN-like lesions are a manifestation of high T. whipplei burden and have more common clinical, pathological, and immunological features than erythema nodosum leprosum (ENL) (57). IRIS in WD manifests as an ENL. The development of EN-like lesions after antibiotic therapy is also probably caused by lymphangiectasias and immune reconstitution secondary to considerable decrease in the number of viable replicating T. whipplei (59).

Patients with WD primarily affecting the muscular layer of the small-bowel wall may be at a risk of small-bowel perforation once IRIS develops. This incidence is the same as for skin diseases (4). This may be related to increased intestinal permeability caused by increased apoptosis of small intestinal mucosal epithelial cells and shorter villi length (5). This risk cannot be excluded with the use of oral steroid hormones. Evidence indicates that T. whipplei mainly infiltrates the submucosa or myenteric layer of the small intestine as PAS-positive material in macrophages containing T. whipplei remnants, and PCR for T. whipplei performed on biopsies shows negative results; this results in disruption to the integrity of the myenteric layer, and the infiltrate consists mainly of CD4+ T cells with a small number of CD8+ T cells (44).

Diarrhea was not previously considered a symptom of WD IRIS (4), although some studies list diarrhea as a clinical presentation in patients with WD IRIS (4, 22, 44). Mounting evidence suggests that the reduced duodenal villus length and microbial translocation observed in patients with IRIS affect barrier dysfunction (5, 44) which may contribute to intestinal barrier leakage and gut microbiota and is another vital causative element of autoimmune disorders (60).

As there is no established laboratory test for WD IRIS, the diagnosis is made by clinical observation (65). The immune response to WD IRIS most frequently occurs in patients previously treated with immunosuppressive drugs, such as analgesics, nonsteroidal anti-inflammatory drugs, steroid hormones, and TNFI, for misdiagnosed inflammatory rheumatism (66). Therefore, it is important to be aware of the possibility of IRIS in patients with WD and a history of any of the above medications. It is also important to consider that steroids suppress inflammatory reactions, and for all patients who present with fever or other inflammatory symptoms after the initiation of treatment for WD of no apparent origin, IRIS should be considered, and appropriate management should be instituted (67). In addition, in HIV patients treated with antiretroviral therapy (ART), ENL skin and eye socket pseudotumors that appeared during the first year of antibiotic therapy were all indications of IRIS. Despite treatment, patients with WD may still develop IRIS as the similar underlying pathology is still present. ENL skin is symbolic of a shift to Th1-mediated inflammation (57).

Compromised intestinal immunity with increased microbial translocation into the systemic circulation has been discussed as a mechanism of immune stimulation in IRIS. Intestinal epithelial dysfunction suggests the need for future research to investigate the length and regenerative potential of the small intestinal mucosa and to monitor inflammation and the MT markers discussed above in patients with CWD (5, 50). In CWD IRIS, reduced duodenal villus length and cytokines produced by non-specific Th1-responses lead to mucosal barrier dysfunction and leaky gut syndrome, which can be reflected by serum markers such as LBP, LPS and sCD14. Local immune activation is reflected by elevated levels of IL-6, CCL2, CCL5, CX3CL1 in the duodenal mucosa. In addition to cytokines, the combination of cerebrospinal fluid IFN-γ and TNF-α concentrations provided a predictive model for tuberculous meningitis (TBM)-IRIS, it has guiding significance for diagnosis and treatment (68). This is what WD IRIS is missing. Only when the auxiliary test is more perfect, the diagnostic prediction model is more likely to be established. In summary, further prospective studies are needed to generate robust evidence on WD IRIS.

The use of corticosteroids as immunosuppressants to treat seronegative arthritis in patients with no clear diagnosis of WD can exacerbate the disease and trigger progression to IRIS (69, 70). When antibiotic therapy fails or the diagnosis of IRIS is clear, oral corticosteroids are generally effective, and several case reports have indicated that oral corticosteroids can alleviate severe symptoms such as fever and subcutaneous nodules and reduce the levels of inflammatory markers such as C-reactive protein (26, 57, 71). However, with the exception of the use of corticosteroids in TB-IRIS (71), current treatment for IRIS is not evidence-based. Moreover, studies on TB-associated IRIS and IRIS associated with HIV infection have generated conflicting evidence regarding therapeutic benefits and appropriate doses of corticosteroids in terms of prevention and mortality rates (72–75). Effective treatment has been reported following the empirical administration of corticosteroids without distinguishing between refractory WD and WD IRIS (30, 56). Corticosteroid treatment for IRIS involves risks and benefits, and it is important to develop more effective and safer drugs (72).

Thalidomide has been successfully used in a case series and has been proposed as the first-line management for IRIS (76, 77) particularly in the presence of ENL reactions (25, 26). Experiments to investigate the mechanisms underlying the effectiveness of thalidomide have not been conducted, and it is speculated to achieve its effects by downregulating TNF-a expression (70). Successful cases of infliximab treatment for IRIS caused by mycobacteria have also been reported (78). However, in all cases, infliximab was used for the treatment of WD before progression to IRIS. This resulted in disease exacerbation with a negative PCR assay result for T. whipplei, which does not exclude the fact that infliximab may contribute to progression to IRIS (79, 80).