Refining the Concept of Microscopic Colitis: HLA Signatures Discriminating Collagenous and Lymphocytic Colitis Free

Inflammatory bowel diseases [IBD] are complex diseases whose aetiopathogenesis has not been entirely clarified despite many years of intensive research efforts. A growing body of evidence indicates a multifactorial pathogenesis including a complex interplay of genetic susceptibility factors as well as various environmental variables including the microbiota and a patient’s lifestyle.¹ For Crohn’s disease [CD] and ulcerative colitis [UC], genome-wide association studies [GWAS] have identified 3220 single nucleotide polymorphisms [SNPs] associated with the risk for these conditions.² While none of these genetic polymorphisms turned out to be a prominent risk factor on its own, identification of these SNPs highlighted the innate immune system and recognition of microbial molecular patterns, autophagy, and the adaptive immune system as relevant players in the pathogenesis of IBD. Further, some SNPs are associated with key therapeutic targets including tumour necrosis factor and the interleukin-23 pathway as well as lymphocyte migration. Therefore, even though the pathogenesis of IBD remains incompletely understood, genetic studies have considerably shaped the way we think about IBD.

In contrast, understanding of the genetic architecture of microscopic colitis [MC] is less well advanced. MC as an umbrella term comprises the subtypes collagenous colitis [CC] and lymphocytic colitis [LC] and is characterized by non-bloody watery diarrhoea, in the absence of relevant macroscopic findings in endoscopy. Histology reveals a subepithelial collagenous band of ≥10 μm [CC] or ≥20 intra-epithelial lymphocytes per 100 epithelial cells [LC] , respectively.^3,4 The incidence of LC and CC increased until 2000 but has been stable since then,⁵ and remains at a lower rate than CD and UC. Since clinical characteristics and treatment strategies [mainly budesonides] for LC and CC are identical, the terms MC/LC and MC/CC are frequently used interchangeably. However, despite these commonalities, the synonymous use of these terms might be conceptually misguided.

In medicine, the precise classification of diseases based on their underlying mechanisms is an ongoing pursuit. When taken to the extremes, treating each patient as a unique phenomenon would be exceedingly inefficient, while treating them all in the same manner would be ineffective. Therefore, diagnostic criteria aim to distil the relevant and characteristic essential features for a group of pathologies. Diagnoses as models for complex realities should be kept as simple as possible but as complicated as necessary. The quest to strike the right balance between simplicity and complexity in disease classification is crucial because it defines the epistemic space of what is conceivable and targetable in medicine. An illustrative case in point is the classification of colorectal cancer according to molecular characteristics. Some subgroups can now be precisely targeted [e.g. by anti-VEGF/VEGFR, anti-EGFR, or immune checkpoint inhibitors].⁶

In light of this, the study of Zheng et al. is commendable since it fundamentally challenges the concept of MC. The authors perform the first genome-wide analysis of genetic susceptibility factors for CC and LC, using large cohorts from Europe and the USA [MC: 2599 cases, 552 343 controls; CC: 1489 cases, 13 487 controls; and LC: 373 cases, 4653 controls]. The authors identify two genetic loci with genome-wide significance for MC. The first locus is within the HLA region on chromosome 6, and the second is on chromosome 16 including two lead SNPs associated with mRNA expression of CLEC16A [C type lectin containing 16A] and RMI2 [RecQ mediate genome instability 2]. Notably, the HLA-related locus on chromosome 6 exhibits strong associations with CC but not with LC. Conversely, the study does not identify a robust genetic predisposition specific to LC. Further analyses revealed the HLA allele DRB1*03:01 as a genetic determinant of CC but not LC. Moreover, three amino acids almost exclusively found in the HLA-DRB1*03:01 allele and located in the peptide binding groove [tyrosine at position 26, asparagine at position 77, and arginine at position 74] were associated with CC [but not LC]. While the association of HLA with MC has been previously demonstrated,^7,8 there has been no separate analysis of LC and CC.

The study by Zheng et al. provides convincing evidence of a distinct genetic basis of CC. Their findings align across different independent cohorts and converge on multiple levels of analysis. The lack of association of HLA-DRB1*03:01 with LC is probably not due to the smaller sample size, since the study was adequately powered to detect a similar size of association with LC.

In addition to its association with MC and CC in the current study, HLA-DRB1*03:01 has been associated with systemic lupus erythematodes,⁹ autoimmune hepatitis type 1 and primary sclerosing cholangitis,¹⁰ autoimmune encephalitis,¹¹ and myasthenia gravis,¹² among others. Notably, some of these conditions are characterized by a fibrosing phenotype. Furthermore, HLA-DRB1*03:01 is a risk factor for typhoid and paratyphoid fever.^13,14In vitro, in the presence of interferon-γ, peptide stimulation of DRB1*03:01 resulted in activation of several pro-inflammatory cascades.¹⁵ Despite these associations, it remains unclear how HLA-DRB1*03:01 increases the risk for CC. Potential mechanisms may involve an increased susceptibility to autoimmune phenomena, an elevated risk for triggering infections, or direct stimulation of pro-inflammatory cascades.

Aligning with a difference in genetic architecture, a previous study revealed unique mucosal lymphocyte compositions in both conditions, in line with divergent pathophysiologies of CC and LC. LC was characterized by lower CD4⁺ and double-positive CD4⁺CD8⁺ mucosal T lymphocytes but higher CD8⁺ and CD4⁺TCRγδ⁺ mucosal T cells compared to CC and controls. However, in both conditions, the levels of regulatory T cells [T_regs] and anti-inflammatory IL-10 were elevated, suggesting common elements of CC and LC, and also common elements in the pathophysiology¹⁶ of both disorders.

However, a reclassification of microscopic disease categories will only prevail in clinical practice if it results in differential management. Both LC and CC respond to the standard treatment budesonide^17,18 and, to the best of our knowledge, no differences regarding the need for long-term treatment with budesonide have been detected.¹⁹ However, other treatments might be tested for budesonide-dependent patients in the future and a differential evaluation for patients with LC and CC should be attempted in those potential trials. Further, according to current understanding, the long-term prognosis of LC and CC also seems similar and the collagenous band in CC typically does not result in relevant intestinal stenosis or fibrosis. Regardless, future clinical and epidemiological studies can consider this genetic evidence and identify its implications.

Taken together, the study by Zheng et al. provides critical and convincing evidence of a distinct genetic and thereby most probably pathophysiological basis of CC.

Funding

No funding was received for this editorial.

Conflicts of Interest

BM has received speaking or travelling fees and/or served on an advisory board with BMS, Abbvie, Takeda, Falk, iQONE, Amgen, MSD, Jansen, and Gilead. B.M. has received unrestricted research grants from MSD, BMS and Nestle.

Author Contributions

Both authors contributed equally and were involved in all steps leading to this paper.

Data Availability

No new data were generated for this paper.

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