Behcet’s disease (BD) is a recurrent and multisystem inflammatory disease that was first described by Dr. Hulusi Behçet, a Turkish dermatologist, in 1937 [1]. The disease typically affects individuals in their third to fourth decade of life and does not display a gender preference. However, severe morbidities are more prevalent in men [2]. With age, disease activity tends to decrease after severe repetitive attacks in the young, productive population. Therefore, BD imposes a considerable economic burden on society. BD is considered an orphan disease in the Western world due to its low prevalence (1–10/100,000), whereas in many developing countries, such as Turkey, BD is more common, with a prevalence of 0.4–4/1000. Japan and Middle Eastern countries also have a higher prevalence of BD ^[3][4][3,4].

Currently, BD is diagnosed only based on clinical findings, and there is no definitive laboratory test to confirm the diagnosis. According to The International Study Group criteria published in 1990 for BD, oral lesions plus two of uveitis, genital lesions, other skin lesions, and a positive skin pathergy test (SPT) are required for BD diagnosis [4]. Although mucocutaneous symptoms are the most common presenting symptoms [5], patients may exhibit vasculitis and multisystemic involvement resulting in significant morbidity ^[3][6][3,6]. Vascular involvement is a defining feature of BD, and both venous and arterial involvement are unique features of the disease. Patients may experience recurrent deep vein thromboses, arterial aneurysms, and intracardiac thromboses [6]. Colchicine is the first-line therapy for mucocutaneous symptoms, and immunosuppressive or immunomodulatory treatments are administered in refractory cases or patients with systemic disease involvement ^[3][6][3,6]. However, current therapeutic techniques may be insufficient in some individuals to control recurring episodes.

BD is a mixed-pattern disease characterized by both autoinflammatory and autoimmune features that develop in genetically susceptible individuals exposed to environmental factors [7]. The genetic background is strong in BD pathogenesis. Familial aggregation is substantial, with risk ratios ranging from 11.4 to 52.5 among siblings in different populations within Turkey ^[8][9][8,9]. A previous study in Korea, with over 21 million individuals in 12 million families, found that the risk of developing Behçet’s disease (BD) was significantly higher among first-degree relatives, especially for twins, with a 165-fold increase [10].

The most significant genetic association related to disease risk is the presence of the human leukocyte antigen (HLA) class I allele HLA-B*51. In recent years, genetic variations in non-HLA genes such as the endoplasmic reticulum aminopeptidase enzyme (ERAP1), interleukin-10 (IL-10), and interleukin-23 receptor/interleukin-12 receptor beta-2 (IL23R/IL-12RB2) have been identified as susceptibility loci for BD [4]. In individuals with genetic susceptibility, external factors such as microbial agents or internal self-antigens like heat shock proteins are suggested as triggers of autoimmune responses, leading to systemic inflammation and the clinical manifestations of BD ^[3][11][3,11]. Immune response aberrations result in the activation of a cytokine cascade and alterations in the levels of cytokines, driving inflammatory cells to migrate to the tissues and causing damage [11].

2. Cytotoxic T Cells (CD8+ T Cells)

HLA-B*51 is the key genetic factor in BD and plays a crucial role in presenting peptides to CD8+ T cells. Consequently, CD8+ T cells are implicated in BD’s pathogenesis. This is supported by increased CD8+ T cells in the aqueous humor and the presence of oligoclonal and clonal expansions of CD8+ T cells in the peripheral blood of BD patients ^[12][13][56,57]. CD8+ T cells release various cytokines, including IL-17, IL-8, and granulocyte–macrophage colony-stimulating factor (GM-CSF), which have diverse effects, such as enhancing neutrophil activation and facilitating the interaction between innate and adaptive immunity in BD’s immunopathogenesis ^[14][50]. In active HLA-B*51+ BD patients, blood samples exhibit a higher proportion of CD8+ T cells compared to healthy individuals and inactive BD patients ^[15][118]. The number of these cells is increased in the aqueous humor of BD patients with ocular involvement ^[16][119]. Studies also indicate that in BD skin lesions, IL-17-secreting T cells predominantly originate from CD8+ T cells rather than CD4+ cells ^[17][116].

3. T Helper 1 Cells

T helper 1 (Th1) cells play a significant role in BD. Comparing active BD patients to both inactive BD patients and healthy individuals reveals an increase in Th1 cells and their associated cytokines, such as interferon gamma (IFN-γ). In ocular non-infectious inflammations like BD, Vogt–Koyanagi–Harada (VKH), and sarcoidosis, there is a notable elevation in Th1 cell infiltration ^[18][120]. Moreover, research by Ye et al. ^[19][121] highlighted the impact of reduced B and T lymphocyte attenuator (BTLA) in the disease’s pathogenesis. This reduction amplifies the activity of Th1 and Th17 cells, worsening ocular inflammation in BD. Exploring this pathway could offer promising avenues for new BD uveitis treatments. Notably, VKH syndrome, the second major cause of uveitis, is unaffected by the decrease in BTLA. Additionally, the mRNA expression of Th1-related cytokines is notably higher in BD patients’ mucocutaneous lesions ^{[1][18][19][20]}[1,120,121,122].

4. T Helper 17 Cells

Th17 cells have garnered significant attention for their involvement in various autoimmune and inflammatory disorders like psoriasis, MS, RA, and IBD ^[21][80]. In a mouse model, the differentiation of Th17 cells from naive T cells is stimulated by IL-6 and transforming growth factor-β (TGF-β). Additionally, TNF-α and IL-1 enhance Th17 differentiation when these cytokines are present. What is particularly intriguing is that while TGF-β typically inhibits most T cell responses and promotes the generation of Tregs, it paradoxically increases the population of Th17 cells ^[22][81]. In a study conducted by Xu et al. ^[23][123], it was revealed that Treg cells can transform into proinflammatory Th17 cells when exposed to IL-6 ^[24][82]. Consequently, Tregs lose their ability to suppress Th17-induced inflammation and may even exacerbate it. This complex interplay underscores the significance of Th17 cells in immune-related diseases. Diverse studies have presented varying perspectives concerning the role of TGF-β in the differentiation of Th17 cells. Some research contends that TGF-β is imperative for the differentiation of Th17 cells, particularly when employing naive T cells derived from cord blood. Furthermore, the concentration of TGF-β emerges as a critical determinant in its functionality, where diminished levels facilitate Th17 differentiation and elevated concentrations promote differentiation of Tregs. Conversely, conflicting research proposes that TGF-β, despite being a requisite for Th17 differentiation in murine models, exerts an inhibitory effect on the genesis of Th17 cells in human subjects. This disparity poses a challenge in the translational applicability of findings from murine disease models to human cases. In conclusion, it is imperative to conduct further rigorous investigations to comprehensively elucidate the nuanced influence of TGF-β on Th17 cell differentiation and its ramifications across a spectrum of pathological conditions ^{[23][25][26][27][28][29]}[123,124,125,126,127,128]. Initially, Th1 cells were presumed to be the central players in BD. However, a substantial body of research has demonstrated an elevated presence of Th17 cells in BD patients, signifying their role in BD pathogenesis ^[30][31][129,130]. BD patients exhibit increased counts of both Th1 and Th17 cells. Moreover, in BD patients, there is a notable upregulation of Th17-associated cytokines, including IL-22 and TNF-α. Furthermore, the transcription factor essential for Th17 cell differentiation, retinoic acid-related orphan receptor γ (RORγt), is found at increased levels in BD patients ^[20][30][32][122,129,131]. In summation, Th17 cells constitute a crucial component in the immunopathological framework of BD, offering valuable insights into the disease’s etiology and holding potential for the identification of innovative therapeutic strategies.

5. Natural Killer T Cells

Upon activation, NKT cells exhibit the secretion of cytokines, including TNF, IFN-γ, IL-4, IL-10, and IL-17. The specific cytokine profile produced is contingent upon factors such as the NKT cell subtype, signal intensity, and the antigen-presenting cells (APCs) involved. NKT cells and their deficiencies serve as valuable diagnostic markers for various diseases and represent an area of active exploration for potential therapeutic and preventive strategies ^{[33][34][35][36]}[132,133,134,135]. In BD patients with ocular involvement, there is an increase in the number of NKT cells, notably the CD8+CD56+NKT subset in the aqueus humor ^[16][119]. However, the data regarding changes in the number of NKT cells in the peripheral blood of BD patients present conflicting results, with some studies indicating an increase while others report a decrease in their numbers ^[37][136]. Furthermore, NKT cells exhibiting high IFN-γ expression are elevated in the cerebrospinal fluid (CSF) of BD patients experiencing neurological symptoms during the active phase of the disease, with a subsequent reduction in these cells when patients transition into remission. Notably, NKT cell activity in the blood displays a concurrent decrease ^[38][137].

6. Gamma-Delta (γδ) T Cells

Gamma-delta (γδ) T cells, distinct from conventional αβ T cells, are integral to the immune response. Typically, γδ T cells lack both CD4 and CD8 markers and do not rely on MHC class I or II molecules for antigen recognition ^[39][138]. During infections, these cells significantly increase in the bloodstream. In mouse models, γδ T cells have emerged as the primary source of IL-17, a potent pro-inflammatory cytokine critical in conditions such as BD, particularly during the onset of inflammation. Two distinct subsets of γδ T cells secrete IL-17. Firstly, natural γδ 17 T cells, known as natural Tγδ17 cells, circulate in the bloodstream, becoming effector cells upon encountering infections. They secrete various cytokines, including IL-17, as part of their immune response. Secondly, induced γδ T17 cells rapidly propagate in response to infection, operating without the need for clonal expansion, yet they significantly contribute to the immune response against pathogens. This dual secretion mechanism of IL-17 underscores the versatility of γδ T cells in immune regulation. Moreover, γδ T cells exhibit a unique ability to function as professional APCs. Multiple investigations have demonstrated their proficiency in activating other immune cells, including both CD4+ and CD8+ T cells, within lymph nodes ^{[40][41][42][43]}[139,140,141,142]. γδ T cell fractions exhibit noteworthy differences in active BD patients when compared to both healthy individuals and those with inactive BD ^[44][75]. These unique T cells are characterized by their release of substantial quantities of cytokines, which result in neutrophil hyperactivity and the induction of Th1 and Th17 cells ^[15][118]. These cells release significant quantities of cytokines, causing neutrophil hyperactivity and the induction of Th1 and Th17 cells ^[45][143]. In the context of BD, it is of particular interest that the Vγ9Vδ2 T cell phenotype experiences a significant elevation in patients. These cells not only produce various inflammatory cytokines, including IL-17, but also cytotoxic molecules such as granzyme A, which are known to play a pivotal role in the pathogenesis of the disease ^[46][47][144,145]. The association between γδ T cells and BD was initially established in the early 1990s, when researchers observed higher levels of γδ T cells within the PBMCs of a group of BD patients ^[48][49][146,147]. When stimulated, these cells are known to release IFN-γ and TNFα ^[50][148]. Interestingly, γδ T cells are believed to have a significant impact on the adaptive immune response by secreting cytokines like interleukin-4 (IL-4) or IFN γ, potentially influencing the immune response toward the Th2, Th17, and Th1 CD4+ T cell phenotypes. Additionally, γδ T cells have been shown to establish efficient interactions with neutrophils and monocytes during acute microbial infections in response to bacterial antigens. Their natural functional diversity and adaptability render them significant contributors to disorders like BD, which affect various compartments of the body. However, despite the potential significance of γδ T cells in BD, the evidence regarding their role in the disease remains somewhat contradictory. While some studies have reported an increase in the population of γδ T cells in BD patients ^{[48][49][50][51]}[146,147,148,149], others have not found a substantial elevation of this specific cell category in PBMCs ^[41][52][53][140,150,151].

7. Regulatory T (Treg) Cells

Regulatory T cells constitute a specialized subset of T cells characterized by the expression of the forkhead box protein P3 (FoxP3), and they play a critical role in maintaining immunological balance while preventing autoimmune responses ^{[54][55][56][57]}[152,153,154,155]. It is evident that any malfunction or reduced quantity of these Tregs can lead to the development of autoimmune disorders, as exemplified by conditions like MS, RA, SLE, and myasthenia gravis ^[54][152]. The role of Tregs in BD has been the subject of investigation, yielding somewhat conflicting results. Some studies suggest a decrease in the number of Treg cells in BD patients, and this reduction is correlated with disease activity, potentially attributed to increased levels of the cytokine IL-21 ^[58][156]. Conversely, another study focusing on the CSF of BD patients with neurologic involvement reported an increase in Treg cell numbers compared to individuals with noninflammatory neurological conditions. However, this increase was associated with a deficiency in suppressing T helper responses, possibly indicating a decline in Treg cell functionality. Furthermore, under inflammatory conditions marked by the presence of IL-1β and IL-2, these Treg cells were proposed to undergo transformation into Th17 cells ^[59][157]. The dual nature of Treg cells in BD, where their numbers may increase in specific contexts, but their functional effectiveness may diminish, highlights the intricate immunological dynamics at play in this disorder.

8. Natural Killer Cells

Natural killer cells (NK cells) constitute a vital component of the innate immune system. NK cells can interact with HLA class I molecules, which are < z < z < Zz < ligands for their KIR receptors. In several autoimmune disorders such as SLE, Sjögren’s syndrome, MS, and RA, there is a consistent pattern of both diminished numbers and impaired functionality of NK cells. NK cells are categorized into two types within the body:

• CD56brightCD16 NK cells, primarily found in the lymph nodes, specialize in cytokine release.
• CD56dimCD16+ NK cells, predominantly present in the blood and inflamed sites, primarily exert cytotoxic effects using proteins like perforin and granzyme, with a diminished capacity for cytokine release compared to the former category ^[60][61][158,159].

Similarly, in BD, a reduction in the quantity of NK cells in the bloodstream is observed, possibly attributed to their migration to inflamed sites. Notably, among the NK cell population, there is an increase in CD56bright NK cells, which are known for cytokine production, particularly IFN-γ ^[62][63][160,161]. NK cells can also be categorized based on the cytokines they produce, falling into five distinct groups: NK-1, NK-2, NK-17, NK-reg, and NK-22, each associated with the release of specific cytokine types such as Th1, Th2, IL-17, IL-10, and IL-22, respectively. Research findings in BD patients reveal an elevated proportion of NK-1 cells, while the numbers of NK-2, NK-17, and NK-reg cells are diminished. Furthermore, investigations have illuminated a notable shift in the NK-1/NK-2 ratio between the active and remission phases of BD. During the active phase, NK-1 predominates, promoting a Th1 immune response, whereas in the remission phase, NK-2 becomes dominant, tilting the immune response toward Th2 activation ^[64][65][66][117,162,163].

9. Neutrophils

BD patients frequently exhibit heightened neutrophil activity and an increased neutrophil count, a phenomenon supported by various investigations. Additionally, granulocyte colony-stimulating factor (G-CSF) levels are elevated in active BD patients, contributing to increased neutrophil apoptosis ^[67][164]. Moreover, several studies have reported an elevated neutrophil-to-lymphocyte ratio in BD patients, with Djaballah Ider’s research highlighting its potential as an indicator of BD and disease severity ^[68][69][165,166]. Le Joncour et al. ^[70][167] have demonstrated elevated levels of neutrophil extracellular traps (NETs) and associated markers like myeloperoxidase (MPO) and cell-free DNA (CfDNA) in BD patients, implicating their role in the disease’s pathophysiology. Notably, NETs have been observed in BD papulopustular lesions ^[17][116]. Neutrophils accumulate significantly in all types of BD lesions, including those affecting the skin, mucocutaneous regions, and eyes. In BD patients, these hyperactive neutrophils induce tissue damage via the oxidative stress mediated by reactive oxygen species (ROS) ^[71][168].