Lymphocytic Colitis: Pathology and Mechanisms

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-09-20

Lymphocytic colitis is a chronic inflammatory pattern of the colonic mucosa defined histologically by an increased number of lymphocytes within the surface and crypt epithelium, accompanied by a largely preserved crypt architecture and little to no neutrophilic crypt destruction. It is best understood as a reaction pattern rather than a single disease, and in dogs it usually appears as one component of a broader chronic enteropathy rather than as a standalone diagnosis.

Lymphocytic colitis matters because it sits at a diagnostic crossroads. The same biopsy can be read as a benign immune infiltrate, as part of inflammatory bowel disease, or as the surface of an emerging lymphoma. Getting the distinction right changes treatment, prognosis, and how aggressively the case is monitored. This article covers the histologic threshold, the immune pathways that drive the infiltrate, and the differential diagnoses that every clinician and pathologist must keep in view.

This article is educational and is not a substitute for veterinary diagnosis or treatment.

What Lymphocytic Colitis Is and Why It Matters

The colonic mucosa is a single layer of epithelial cells sitting on a basement membrane, with a lamina propria beneath it that normally contains a resident population of lymphocytes and plasma cells. In health, that population is small, organized, and quiet. In lymphocytic colitis, the balance shifts: lymphocytes move into the epithelium itself, and the lamina propria fills with mononuclear inflammatory cells.

Two features define the pattern:

1. Increased intraepithelial lymphocytes (IELs). Lymphocytes infiltrate between epithelial cells, especially along the surface epithelium and the upper crypt.
2. Preserved architecture. The crypts keep their normal shape, spacing, and goblet cell population. There is minimal neutrophilic cryptitis, meaning neutrophils do not stream into the crypt epithelium and destroy it.

That combination separates lymphocytic colitis from the erosive and suppurative colitides, where crypt destruction and neutrophils dominate. It also separates it from the fibrosing pattern of collagenous colitis, where a thickened subepithelial collagen band is the defining lesion.

In dogs, the term most often used in the literature is lymphocytic-plasmacytic colitis (LPC). LPC is described as a well-recognized clinical and pathological entity in the dog, associated with altered immune cell populations and cytokine expression profiles [1]. The plasma cell component is often prominent, which is why the older literature pairs the two cell types. Modern usage increasingly separates the lymphocytic pattern from the plasmacytic pattern, because the two can occur independently and may reflect different immune drives.

The Histologic Threshold: Counting Cells and Reading Architecture

The Intraepithelial Lymphocyte Count

The single most useful number in this diagnosis is the IEL count, expressed as lymphocytes per 100 epithelial cells. In human pathology, the accepted threshold for lymphocytic colitis is generally more than 20 IELs per 100 epithelial cells, with normal colonic mucosa typically showing fewer than 5 to 10. This threshold is a convention, not a law of biology, and it must be applied with the same fixation, section thickness, and staining method across a laboratory.

Practical points for counting:

• Count on well-oriented sections, ideally perpendicular to the mucosal surface.
• Evaluate the surface epithelium and the upper crypt, where IELs concentrate.
• Use a consistent denominator (100 epithelial cells) so counts are comparable between cases and between serial biopsies in the same patient.
• Avoid areas of mechanical artifact, where epithelium is crushed or tangentially cut.

A grading system developed for canine lymphocytic-plasmacytic colitis scored colonic mucosal samples on a scale of 0 to 5 based on the quantity of lymphocytes and plasma cells in the lamina propria, epithelial changes, and the presence of ulcers and erosions [2]. A grade of 2.0 or less was considered normal. That system assigned normal grades to 77 of 78 samples from clinically normal dogs and to 28 of 48 samples from dogs with diarrhea [2]. The overlap is instructive: cellularity alone does not equal disease, and a subset of dogs with diarrhea have histologically normal colons.

Architecture and the Neutrophil Question

The second pillar of the diagnosis is what is not present.

• Crypt architecture is preserved. Crypts remain parallel, evenly spaced, and of normal length. There is no crypt distortion, branching, or loss.
• Neutrophilic cryptitis is minimal or absent. Neutrophils may be present in small numbers in the lamina propria, but they do not invade crypt epithelium or form crypt abscesses.
• Goblet cells are retained. Paneth cell metaplasia, a marker of chronic injury in the proximal colon, is not a feature.
• Erosions and ulcers are absent in uncomplicated disease. Their presence signals a different or superimposed process.

When crypt distortion, crypt abscesses, and ulceration are present together, the pattern shifts toward ulcerative colitis or a severe IBD phenotype, and the differential changes substantially.

Mechanisms: How the Lymphocytic Infiltrate Arises

Antigen Handling and the Epithelial Barrier

The colonic epithelium is a barrier, and the apical junction complex is the machinery that seals the spaces between cells. That complex includes tight junction proteins (ZO-1, occludin, claudin-2) and adherens junction proteins (E-cadherin, beta-catenin). In normal canine colon, these proteins show a distribution similar to that described in humans and rodents, with one notable species difference: claudin-2 labeling is present in normal canine colonic crypt epithelium and decreases in intensity from the distal to the proximal crypt, becoming barely detectable at the luminal surface [1].

In dogs with idiopathic LPC, expression of ZO-1, occludin, E-cadherin, and beta-catenin changes little. Claudin-2, however, increases markedly in the proximal crypt and luminal colonic epithelium [1]. Claudin-2 forms a pore that allows paracellular flux of water and small cations, so its upregulation at the luminal surface is a plausible route by which luminal antigens reach the immune system. Barrier leakiness and immune activation become a self-reinforcing loop: antigen passage drives inflammation, and inflammation alters junctional protein expression.

Innate Sensing: NOD2 and NF-kappaB

Nucleotide Oligomerization Domain Two (NOD2) is an intracellular pattern recognition molecule that detects bacterial fragments and triggers a host defense response through activation of the transcription factor NF-kappaB, followed by proinflammatory cytokine production. In dogs with LPC, NOD2 mRNA expression in colonic mucosa was approximately 63% greater than in healthy controls, and NF-kappaB binding activity was approximately 45% higher in inflamed mucosa [3]. NOD2 mRNA expression and NF-kappaB activation are increased in mucosal biopsies of LPC dogs compared with controls [3]. No correlation was found between these markers and the clinical disease activity index, which suggests the innate sensing arm is switched on but does not track symptom severity directly [3].

The Cytokine Picture: Muted and Mixed

Human IBD classically splits into a Th1/Th17-driven Crohn's pattern and a Th2-skewed ulcerative pattern. Canine LPC does not follow that script neatly. When investigators measured mRNA for T helper cytokines (IFN-gamma, IL-4, IL-17, IL-10) and proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha, IL-8, IL-12, IL-23) in colonic mucosa from LPC dogs, no significant differences were detected between affected dogs and controls except for IL-23p19 [4]. Dogs with LPC failed to express a predominant cytokine profile in inflamed colonic mucosa, in contrast to human IBD [4].

That finding is a useful corrective for students. A dense lymphocytic infiltrate does not automatically mean a polarized cytokine storm. The canine colonic immune response in LPC appears broad and comparatively undifferentiated at the transcript level.

Lymphocyte and Plasma Cell Populations

Immunophenotyping shows what the infiltrate is made of. In healthy dogs, CD3+ T cells predominate in colonic mucosa. In dogs with LPC, CD3+ T cells and IgA-containing cells are the most numerous populations. IgA- and IgG-containing cells and CD3+ T cells are significantly more numerous in the colonic mucosa of dogs with LPC than in healthy dogs [5]. IgG- and IgM-containing cells are considerably less numerous than the other two cell types in both groups [5].

A separate immunohistochemical study of endoscopic colon biopsies from dogs with plasmacytic-lymphocytic colitis found a characteristic infiltrate rich in lymphocytes and plasma cells in the lamina propria in all biopsies, and concluded that IgG is the major antibody in the immune response of dogs with this condition [6]. The two studies emphasize different immunoglobulins, which reflects differences in technique, case selection, and the specific question asked. The consistent theme is a mixed B cell and T cell response with a substantial plasma cell component.

Comparative Mechanisms: What Other Species Show

Humans. Microscopic colitis comprises collagenous colitis and lymphocytic colitis, two clinically indistinguishable entities with different immunopathology. Collagenous colitis associates with HLA genes and displays a Th1/Tc1 to Th17/Tc17 profile with pericryptal myofibroblast activity, water malabsorption, and secondary fluid loss from altered osmoregulation. Lymphocytic colitis lacks those genetic associations and displays a Th1/Th2 profile with paracellular and transcellular permeability defects [7]. Lymphocytic colitis further subdivides into a channelopathic form, driven by altered ion and organic acid transport that may follow drug exposure, and an inflammatory form involving moderate immune responses [7].

Chemokine profiling supports the idea that these are distinct diseases. In active disease, both collagenous colitis and lymphocytic colitis show a mixed chemokine profile with significantly enhanced gene or protein expression of CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX3CL1, plus the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX3CR1 [8]. One difference stands out in remission: enhanced chemokine and receptor levels in lymphocytic colitis in histologic remission remain similar to active lymphocytic colitis, whereas collagenous colitis in remission shows almost normalized levels [8]. That finding supports the hypothesis that collagenous colitis and lymphocytic colitis are two different entities based on differences in their immunoregulatory responses [8].

Cytotoxic T cell biology is also in play. Granzyme B and CCL5 levels were higher in active collagenous colitis than in ulcerative colitis, while several markers (APRIL, BAFF, BCMA, CCL20, CXCL8, chitinase 3-like 1, pentraxin-3, Fas, and IL-33) were higher in ulcerative colitis than in microscopic colitis [9]. Increases in 4-1BB and perforin in microscopic colitis compared with controls were lower than in ulcerative colitis, and levels of gp130 and IL-6R-alpha were decreased in microscopic colitis but increased in ulcerative colitis compared with controls [9]. The pattern is one of increased cytotoxic surveillance without the full destructive machinery of ulcerative colitis.

Cats. Lymphocytic-plasmacytic colitis is recognized in cats. In a case series of 14 cats, purebred cats were affected significantly more often than nonpurebred cats, mean age at onset was 5.1 years, and hematochezia (13 cats) and diarrhea (11 cats) were the most common signs [10]. Endoscopic examination found petechia and hyperemia of the colonic mucosa in 7 of 8 cats examined [10]. Most cats were eventually maintained on dietary management alone [10].

Horses. The equine literature describes a lymphocytic-plasmacytic enterocolitis pattern, often with a protein-losing component, and the histologic approach parallels the small animal one: quantify the infiltrate, assess architecture, and exclude lymphoma.

Baboons. A distinct entity termed cryptal lymphocytic colitis has been reported in a baboon that died of chronic, intractable diarrhea. Gross examination showed edema and signs of chronic inflammation throughout the colon, and histology showed marked lymphocytic infiltration within the colonic epithelium covering the crypts [11]. This is a reminder that the pattern is not confined to domesticated species and that comparative pathology can reveal variants of the same process.

How the Diagnosis Is Made in Practice

Endoscopy and Biopsy

Colonoscopy with multiple mucosal biopsies is the standard approach. Lesions may be subtle: hyperemia, petechiae, loss of vascular pattern, or a grossly normal mucosa. Because the disease can be patchy, multiple biopsies from several colonic segments increase yield. Biopsies must be oriented and handled gently, since crush artifact destroys the epithelial detail needed for IEL counting.

Histopathology

The pathologist reports the IEL count, the character and density of the lamina propria infiltrate, crypt architecture, the presence or absence of neutrophilic cryptitis, and any epithelial injury. A semiquantitative grading scheme can be applied to track severity and response over time [2].

Immunohistochemistry

Immunohistochemistry (IHC) uses labeled antibodies to identify specific cell types in tissue sections. In colonic mucosa, CD3 marks T cells, CD20 or CD79a marks B cells, and MUM1 or CD138 marks plasma cells. IHC helps in three ways:

• It confirms that the infiltrate is predominantly T cell or mixed rather than a uniform population.
• It reveals whether the infiltrate is expanding into the epithelium in a way that suggests neoplasia.
• It supports the search for an aberrant phenotype, such as loss of normal T cell markers, which raises concern for lymphoma.

Clonality Testing

Clonality testing (often called PCR for antigen receptor rearrangements, or PARR) detects whether a lymphocyte population is monoclonal, meaning it arose from a single cell, or polyclonal, meaning it is reactive. A monoclonal result supports lymphoma. A polyclonal result supports a reactive process. Clonality testing is most useful when paired with histology and IHC, because neither test alone is definitive. A reactive infiltrate can occasionally show a clonal result, and a lymphoma can occasionally evade detection.

Ancillary Testing

Fecal calprotectin, a neutrophil-derived protein, is used in human medicine as a marker of intestinal inflammation. In one cohort of 234 calprotectin measurements during symptomatic microscopic colitis, 29.0% of levels exceeded 150 mcg/g and 18.4% exceeded 250 mcg/g [12]. Elevated levels were associated with nocturnal bowel movements and fecal incontinence [12]. This marker is not a substitute for biopsy and is not established as a routine veterinary test, but it illustrates the direction of non-invasive monitoring.

Differential Diagnosis: A Practical Table

The table is a guide, not a decision rule. Mixed patterns occur, and a single biopsy may show features of more than one column.

Clinical Relevance, Limitations and Common Mistakes

Lymphocytic colitis in dogs is usually a component of chronic enteropathy rather than a standalone diagnosis. That framing matters because treatment targets the whole patient: diet, the microbiome, the immune system, and any underlying trigger. A biopsy report that names lymphocytic colitis does not by itself dictate a specific drug or diet.

Common mistakes:

• Treating the IEL count as absolute. The >20 per 100 epithelial cells threshold is a convention. Counts must be interpreted with the laboratory's own reference range and the biopsy technique used.
• Ignoring the plasma cell component. Many canine cases are lymphocytic-plasmacytic, and the plasma cell population may carry equal diagnostic weight.
• Overcalling lymphoma. A dense lymphocytic infiltrate with epithelial invasion can mimic lymphoma. IHC and clonality testing are needed before making that leap.
• Under-calling clinically significant disease. A subset of dogs with diarrhea have normal or near-normal histology [2]. Histology and clinical signs must be integrated.
• Assuming a single cytokine profile. Canine LPC does not show the clean Th1/Th17 or Th2 polarization seen in human IBD [4].
• Forgetting species differences. Claudin-2 distribution in normal canine colon differs from humans [1], and lymphocytic colitis in humans has different genetic associations and immunoregulatory behavior than collagenous colitis [7].

Limitations of the current knowledge base include the small size of most veterinary studies, the variability in biopsy protocols, and the absence of a validated veterinary disease activity index that maps cleanly onto histology. Individual cases require a veterinarian who can integrate history, examination, laboratory data, imaging, and biopsy findings.

Quick Review

1. Lymphocytic colitis is defined by increased intraepithelial lymphocytes (often more than 20 per 100 epithelial cells) with preserved crypt architecture and minimal neutrophilic cryptitis.
2. In dogs it usually appears within a chronic enteropathy, often as lymphocytic-plasmacytic colitis rather than an isolated diagnosis.
3. Barrier dysfunction is part of the mechanism: claudin-2 increases in the proximal crypt and luminal epithelium in affected dogs [1].
4. Innate sensing is activated: NOD2 mRNA and NF-kappaB activity are increased in colonic mucosa of dogs with LPC [3].
5. The cytokine profile in canine LPC is mixed and lacks the dominant polarization seen in human IBD, with IL-23p19 the main exception [4].
6. Immunohistochemistry and clonality testing are the key tools for separating reactive lymphocytic infiltrates from alimentary lymphoma.
7. Species differences are real: humans, cats, horses, and baboons all show variations on the pattern.

Frequently Asked Questions

What is lymphocytic colitis?

Lymphocytic colitis is a chronic inflammatory pattern of the colon marked by increased lymphocytes within the epithelial layer, with preserved crypt architecture and little neutrophilic crypt damage.

How is it diagnosed?

Diagnosis requires colonic biopsy with histologic counting of intraepithelial lymphocytes, assessment of crypt architecture, and exclusion of other patterns such as collagenous colitis, ulcerative colitis, and lymphoma.

Is lymphocytic colitis the same as inflammatory bowel disease?

No. It is a histologic pattern that can be a component of inflammatory bowel disease or chronic enteropathy, but the terms are not interchangeable.

Can lymphocytic colitis be confused with lymphoma?

Yes. A dense lymphocytic infiltrate can resemble lymphoma on routine stains, so immunohistochemistry and clonality testing are used to distinguish a reactive process from a clonal neoplastic one.

Does lymphocytic colitis occur in cats and other species?

Yes. It is described in cats, horses, and non-human primates, with species-specific differences in presentation and histology.

What is the difference between lymphocytic colitis and collagenous colitis?

Lymphocytic colitis is defined by increased intraepithelial lymphocytes, while collagenous colitis is defined by a thickened subepithelial collagen band. They are considered distinct entities with different immunoregulatory profiles.

Related Articles

• Edema and Shock: Pathophysiologic Mechanisms
• Cell Injury Mechanisms and Morphologic Patterns
• Colitis In Dogs Treatment
• Neoplasia: Mechanisms of Carcinogenesis and Classification
• Environmental Toxins and Mechanisms of Cellular Injury
• Canine Lymphocytic Plasmacytic Enteritis: Diagnosis and Management

Sources

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2. A grading system for lymphocytic plasmacytic colitis in dogs.
3. NOD2 mRNA expression and NFkappaB activation in dogs with lymphocytic plasmacytic colitis.
4. Evaluation of selected cytokine gene expression in colonic mucosa from dogs with idiopathic lymphocytic-plasmacytic colitis.
5. Colonic lymphocyte and plasma cell populations in dogs with lymphocytic-plasmacytic colitis.
6. Immunohistological study of IgA, IgG and IgM in endoscopic biopsies of dogs with plasmacytic-lymphocytic colitis.
7. Dissecting Microscopic Colitis Immunopathophysiology: Insights From Basic Research.
8. Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment.
9. Increased Colonic Levels of CD8+ Cytotoxic T lymphocyte-Associated Mediators in Patients With Microscopic Colitis.
10. Lymphocytic/plasmacytic colitis in cats: 14 cases (1985-1990).
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