Corneal Clarity
Zooming In on the Mast Cell
Besides ocular allergy, it can be friend or foe in many other presentations.
By: Thomas John, MD
In ophthalmology, the three domains of primary interest are ocular inflammation, infection and surgical vision augmentation. Zooming in from a macro to a micro or cellular level, in this column I will focus on the mast cell, which for the most part occupies the center stage as a player in these three domains of ophthalmic interest.
Mast cells are well known for their role in ocular allergy (Figure) and anaphylaxis. However, their critical role in both the defense against invasive pathogens and wound healing is not so well known. Here, I’ll take a closer look at the mast cell’s functions.
Mast Cell Profile
While we’ve viewed mast cells to be very similar to basophils (white blood cell), they are quite different because each originates from different cell lines. Mast cells come from bone marrow precursors expressing the CD34 molecule. Paul Ehlrich initially described them in 1878. Hematopoietic stem cells give rise to mast cells that circulate as immature progenitors, which in turn finally mature locally in the peripheral sites.
In the eye, mast cells are present in the conjunctiva, uveal tract (especially the choroid) and iris. Mast cells are also present in the optic nerve.
Two types of mast cells exist: connective tissue-associated and mucosa-associated mast cells. T-cells influence mucosal mast cell activities. Mast cells primarily reside around blood vessels and nerves, hence their vascular effect increases vascular permeability and edema while their neuronal effect causes itching or pain.
It is interesting to note that these mast cells are primarily located in regions such as the conjunctiva and ocular surface, and non-ocular locations including the nose, mouth, lungs, gastrointestinal tract and skin — that is, where the human body is exposed to the external environment.
Because the eye can be involved in systemic diseases, this understanding of mast cell distribution in the human body is worthy of our attention.
The Role We Know Best
Mast cells play a major part in allergic conjunctivitis, so mast-cell stabilizers have a profound effect in managing ocular allergy. In all forms of allergic conjunctivitis, the number of mast cells on the ocular surface increases. Activation of these mast cells plays a significant role in the development of ocular allergic response, which consists of two phases — the early and late inflammatory phase.
Of interest to the ophthalmologist is the role of mast cells in autoimmunity, especially in rheumatoid arthritis that can contribute to dry eyes.
Research has demonstrated that mast cells are involved in inflammatory cell recruitment to the joints in rheumatoid arthritis and skin in bullous pemphigoid. In addition, there is a rare condition with mast-cell proliferation called mastocytosis. Mastocytosis can exist either in a cutaneous form, or systemically, and the condition can result in a multi-organ involvement.
Toulidine blue stain highlights mast-cell granules. The secretory granules within mast cells contain preformed mediators. Upon activation of mast cells, these preformed mediators are released within minutes into the extracellular environment.
The primary mast-cell granular constituents include histamine, carboxypeptidase A, serine proteases and proteoglycans heparin and chondroitin sulfate E. Besides these preformed mediators, there also exist de-novo synthesized lipid mediators that include the lipoxygenase products leukotriene C4, D4 and E4, and the cyclooxygenase product prostaglandin D2.
Figure: Seasonal allergic conjunctivitis showing conjunctival injection, chemosis and tearing.
Beyond Allergy
The role of the mast cell in bacterial and viral infections is not widely known, largely because its role in ocular allergy overshadows other less known functions. Researchers have shown that mast cells can enhance host resistance and survival in several bacterial infections.1-5
Mast cell-related host defense against microorganisms include bacterial phagocytosis,5 and endogenous mediators such as neurotensin6 and endothelin,1,7 which are subject to protelytic degradation prior to reaching toxic levels. Granulocyte function or recruitment are also augmented by the mast cells and hence the host defense.1,4,6,8,9
Thus, mast cells appear to have an important role in helping to clear bacteria and increase survival. They may also limit collateral tissue damage.10
Additionally, mast cells also seem to play a role in viral infection, although the biologic significance of their contributions is not fully understood. Viruses including HIV can infect the mast cell,11 and the interactions between mast cells HIV, IgE and TLR need further study. Many HIV-infected patients have elevated levels of IgE.10,12
Further, HIV-1gp120 and Tat proteins promote the functional activation and migration of mast cells.12 Some evidence supports the contention that mast cells can act as a reservoir of persistent HIV infection.10,11
Mast cells also appear to play a role in certain parasitic infections. For instance, evidence has shown mast cell activation in proximity to parasites.13
A Two-Plane Operation
When a pathogen invades the human body, our immune system plays a role in its defense. Our immune system may be viewed at these two different planes:
► Non-specific or innate. This refers to the first-line of defense, natural barriers such as the skin, the acidity of oils on our skin and stomach acid. Once a pathogen passes the first-line of defense and enters the body, then the second-line of defense, also non-specific, tries to stop the invasion. This involves the inflammatory response. The process of phagocytosis by leukocytes (neutrophils, macrophages, dendritic cells) also tries to stop the invading pathogen.
► Specific immune system. The main cells that play a role in the adaptive immune system, also known as acquired immune system, are also white blood cells. Namely, these are the lymphocytes, which include the B-lymphocytes and the T-lymphocytes.
While the B-lymphocytes are produced in the bone marrow, the T-lymphocytes, also produced in the bone marrow, mature in the thymus.
The term B-lymphocytes has its origin in birds in the bursa of Fabricius, as Hieronymus Fabricius first described in 1621. However, mammals are devoid of such an organ, and the bone marrow is usually the nidus of hematopoiesis and B-cell development. Thus, “B” may also refer to the bone marrow.
The B-lymphocytes take part in the humoral response, while the T-lymphocytes participate in the cell-mediated response. There are helper T-cells and cytotoxic T-cells. Helper T-cells aid in activating and further amplifying the humoral response. Once a pathogen enters the body, the pathogen is initially in the bodily fluids before it invades the cells.
The humoral response can play a role in our defense during this stage of infection. However, if the pathogen survives all the initial defensive attacks and proceeds to infect the cells in our body, the cell-mediated response begins to play a role in attempting to destroy these infected cells. The mast cell seems to have the capability of influencing our immune response.
Mast Cell as Healer
In addition to its recognized role in ocular allergy, and more recently in infection, the mast cell plays a role in wound healing. Mast cells participate in three phases of wound healing:14
• Inflammatory reaction.
• Angiogenesis.
• Extracellular-matrix resorption.
Additionally, mast cells residing in tissues can become activated following traumatic injury and also via immune-mediated mechanisms.
Besides the well-known role of mast cells in allergy, they also may be involved in many other ancillary functions, including antigen presentation and interactions with other immune cells that can result in the enhancement or suppression of innate or adaptive immune responses.10,15,16
We must remember before we zoom out of the micro level that cells can be either our friend or foe. The mast cell is no exception. OM
References
1. Thakurdas SM, Melicoff E, Sansores-Garcia L., Moreira DC, Petrova Y, Stevens R L and Adachi R. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J Biol Chem. 2007;282:20809-20815.
2. Kalesnikoff J and Galli SJ. New developments in mast cell biology. Nat Immunol. 2008;9:1215-1223.
3. Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature. 1996;381:77-80.
4. Dawicki W, Marshall JS. New and emerging roles for mast cells in host defence. Curr Opin Immunol. 2007;19:31-38.
5. Hofmann AM, Abraham SN. New roles for mast cells in modulating allergic reactions and immunity against pathogens. Curr Opin Immunol. 2009;21:679-686.
6. Piliponsky AM, Chen CC, Nishimura T, Metz M, Rios EJ, Dobner PR, Wada E, et al. Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis. Nat Med. 2008;14:392-398.
7. Maurer M, Wedemeyer J, Metz M, Piliponsky AM, Weller K, Chatterjea D, Clouthier, DE, et al., Mast cells promote homeostasis by limiting endothelin-1-induced toxicity. Nature. 2004;432:512-516.
8. Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature. 1996;381:77-80.
9. Sutherland RE, Olsen JS, McKinstry A, Villalta SA, Wolters PJ. Mast cell IL-6 improves survival from Klebsiella pneumonia and sepsis by enhancing neutrophil killing. J Immunol. 2008;181:5598-5605.
10. Galli SJ, Tsai M. Mast cells in allergy and infection: Versatile effector and regulatory cells in innate and adaptive immunity. Eur J Immunol. 2010;40:1843-1851.
11. Sundstrom JB, Hair GA, Ansari AA, Secor WE, Gilfillan AM, Metcalfe DD, Kirshenbaum AS. IgE-FcepsilonRI interactions determine HIV coreceptor usage and susceptibility to infection during ontogeny of mast cells. J Immunol. 2009;182:6401-6409.
12. Marone G, Florio G, Petraroli A, Triggiani M, de Paulis A. Role of human FcepsilonRI1 cells in HIV-1 infection. Immunol Rev. 2001;179:128-138.
13. Anthony RM, Rutitzky LI, Urban JF, Stadecker MJ, Gause WC. Protective immune mechanisms in helminth infection. Nat Rev Immunol. 2007;7:975-987.
14. Trabucchi E, Radaelli E, Marazzi M, Foschi D, Musazzi M, Veronesi AM, Montorsi W: The role of mast cells in wound healing. Int J Tissue React. 1988;10:367-72.
15. Sayed BA, Christy A, Quirion MR, Brown MA. The master switch: the role of mast cells in autoimmunity and tolerance. Annu Rev Immunol. 2008;26:705-739.
16. Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol. 2008;8:478-486.
Thomas John, MD, a world leader in lamellar corneal surgery, is a clinical associate professor at Loyola University at Chicago, and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. E-mail him at tjcornea@gmail.com. |