**3. Pathogenesis of PUK**

#### **3.1 Features of the peripheral cornea**

The peripheral cornea has unique anatomical and physiological features, some of which make it more susceptible to hypersensitivity reaction, autoimmune processes, and ulcerations [1]. Different from the central part of the cornea, the peripheral cornea has a greater thickness (up to 0.7 mm), and the epithelium is firmly adherent to the underlying basement membrane [17]. Epithelial stem cells are more concentrated, have the highest proliferation rate whereas endothelial cells have maximum myogenic activity [17, 18]. Moreover, higher levels of the cell surface-associated glycoprotein Mucin-4 (MUC-4) gene, which has epithelial-protective activity and is responsible for regulating the renewal and differentiation of epithelial cells, have been found in the corneal periphery [19]. Furthermore, it has less innervation, and therefore sensitivity is lower in this region [18].

Differently from the avascular central cornea, where the main nutritional sources are the tear film and aqueous humor, the limbus and peripheral cornea obtain nutrients from the vascular arcade that originates from the anterior ciliary arteries extending approximately 0.5 mm into the clear cornea [20]. Perilimbal vascular and lymphatic arcades, along with the adjacent conjunctiva, provide a reservoir of different inflammatory cells and cytokines [1, 3].

As a result of tight collagen bundle packing and vascular architecture at the periphery of the cornea, there is an accumulation of high molecular weight compounds (such as IgM, complement component 1 (C1)) and immune complexes, which are unable to diffuse into the central cornea from the limbal vessels [21, 22]. Besides, compared to the central cornea, there is a higher density of Langerhans' cells, which are highly potent antigen-presenting dendritic cells [22].

#### **3.2 B-cell and antibodies**

Patients with RA demonstrate loss of normal B-cell tolerance for their own antigens; some have serum IgM directed against their own IgG (RF), and the immune complexes aggregate at the corneal periphery causing complement activation and corneal damage [1]. Anti-CCP antibodies, present in some RA patients, are associated with a more severe presentation of PUK [23]. In SLA, impaired immune tolerance triggers the production of ANA that form immunocomplexes by which the clearance of apoptotic cells is impaired and subsequently causes profound tissue damage [24].

In GPA, ANCA also binds to both monocyte and neutrophil receptors, increasing the release of destructive enzymes and proinflammatory cytokines [25] (in the course of various corneal inflammatory diseases, including PUK, upregulated expression of interleukin (IL)-6, IL-1b and tumor necrosis factor (TNF)-α is important) [3]. Among patients with PUK during RA and GPA, antibodies targeting directly the corneal epithelium have been identified [26, 27].

Besides the production of antibodies, B-cells are involved in producing cytokines that affect pathological T-cell response, regulate Th1/Th2 balance, and participate in presenting antigenic peptides via major histocompatibility complex (MHC) class II molecules [28].

#### **3.3 Complement and innate immunity**

Circulating antigen-antibody complexes act on C1, the first element of the classical complement activation pathway [29]. The large size of C1 inhibits its diffusion through the cornea, so it persists at the periphery and corneal stroma [21]. During the activation of complement cascade, C3a and C5a polypeptides are formed, demonstrating chemotactic activity, particularly on neutrophils and eosinophils. Ultimately, the complement system causes stromal destruction and lysis of cell membranes [30, 31]. Studies of corneas affected by PUK have shown a large number of various proinflammatory cells of the innate immune system, e.g., neutrophils, mast cells, plasma cells, eosinophils, which are a source of destructive and collagenolytic enzymes that trigger corneal damage [3].

#### **3.4 T-cell immunity**

T-cell response is crucial in protection against pathogens but also plays an important role in immunopathological conditions, e.g., the number of CD4 cells is significantly greater among patients with RA [32]. Adaptive T-cell-mediated immunity has been shown to be involved in PUK formation. T-cells can cause tissue damage either directly or through dysregulated autoantibody and proinflammatory cytokine production [3].

#### **3.5 Matrix metalloproteinases**

Metalloproteinases (MMPs) are proteolytic enzymes that cause disruption and disintegration of specific extracellular matrix components. MMPs can be divided according to substrate specificity: collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. The release of cytokines such as IL-1 from inflammatory cells enables stromal keratocytes to produce MMP-1 and MMP-2. The imbalance between MMPs and their respective tissue inhibitors (TIMPs) results in high collagenase activity, increased tissue destruction, ulceration as well as disruption of the tissue repair process by breaking down the newly formed noncrosslinked collagen [33].

MMP-1 (produced by macrophages and fibroblasts) and MMP-8 (produced by neutrophils and invading inflammatory cells near the limbus) play a pathogenic role in the course of PUK, initiating the hydrolysis of fibrillar type 1 collagen, the main component of corneal stroma. The gelatinases (MMP-2, -9) can cleave basement membrane components (collagen type IV, VII; fibronectin, laminin) and stromal collagen types IV, V, VI, the core protein decorin, and denatured collagens [34].

### **4. Clinical presentation**

The majority of PUK occurs unilaterally and affects one segment of the cornea, while it rarely presents in both eyes, in such cases, the lesions are usually asymmetrical [13]. The eye redness, photophobia, tearing, and pain are the initial symptoms of PUK. Pain is an important feature and can vary in intensity. Deterioration of visual acuity can occur in the active phase of the disease as a result of inflammation or in the chronic phase secondary to corneal astigmatism with corneal opacity [4].

## *Peripheral Ulcerative Keratitis Associated with Autoimmune Diseases DOI: http://dx.doi.org/10.5772/intechopen.112140*

Slit lamp examination demonstrates peripheral, crescentic destructive inflammation at least 2 mm from the limbus, associated with epithelial defect and corneal thinning. The leading edges are undermined, infiltrated, and de-epithelialized. The involvement of the lower part of the cornea is reported to be prevalent compared to the upper part. The spread is circumferential and occasionally central. The ulceration initially involves the superficial one-third of the cornea and may enlarge over time resulting in corneal perforation. It should be noted that the epithelial defect will predispose to secondary infection [4, 13].

Analysis of anterior segment optical coherence tomography (AS-OCT) is useful in the monitoring of disease activity and the evolution of changes. In the active phase, the absence of corneal epithelium, scrambled appearance of the anterior stroma, and heterogeneous stromal reflectivity are observed. As the inflammation intensity declines, irregular hyporeflective epithelium, a smoother anterior stroma, and a homogeneous hyperreflective stroma can be seen. On the other hand, healed PUK lesion is characterized by a filled corneal defect with a hyporeflective thick epithelium, a demarcation line, and the persistence of the hyperreflective underlying stroma [35, 36].

PUK may clinically present as:


**Figure 1.** *Crescent-shaped peripheral corneal thinning.*

**Figure 2.** *360 degrees of peripheral corneal thinning.*

**Figure 3.** *Sectorial corneal thinning with superficial vascularization.*

**Figure 5.** *Corneal perforation and iris tissue prolapse.*

d. Corneal perforation or impending perforation is uncommon but is the most serious complication of PUK. Occasionally, accompanying iris prolapse in the area of corneal defect may be observed (**Figure 5**) [5].
