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DENTAL SCIENCE - REVIEW ARTICLE
Year : 2014  |  Volume : 6  |  Issue : 5  |  Page : 9-12  

Immunology of oral candidiasis


1 Department of Oral and Maxillofacial Pathology, Vivekanandha Dental College for Women, Tiruchengode, Namakkal, Tamil Nadu, India
2 Department of Oral and Maxillofacial Pathology, Madha Dental College and Hospital, Chennai, Tamil Nadu, India
3 Department of Oral and Maxillofacial Surgery, Madha Dental College and Hospital, Chennai, Tamil Nadu, India

Date of Submission30-Mar-2014
Date of Decision30-Mar-2014
Date of Acceptance09-Apr-2014
Date of Web Publication25-Jul-2014

Correspondence Address:
Dr. Janardhanam Dineshshankar
Department of Oral and Maxillofacial Pathology, Vivekanandha Dental College for Women, Tiruchengode, Namakkal, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-7406.137251

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   Abstract 

A successful pathogen is one that is able to effectively survive and evade detection by the host immune defense. Oral candidiasis has adopted strategies, which evade host defense and eventually cause disease in at-risk patients. Host defense against infections with Candida spp. depends on rapid activation of an acute inflammatory response by innate immunity, followed by an incremental stimulation of specific immune responses mediated by T-cells (cellular immunity) or B-cells (humoral immunity). Understanding these complex pathways of immune evasion can potentially contribute to the development of novel therapeutic strategies against oral candidiasis.

Keywords: Cellular immunity, humoral immunity, oral candidiasis


How to cite this article:
Dineshshankar J, Sivakumar M, Karthikeyan M, Udayakumar P, Shanmugam K T, Kesavan G. Immunology of oral candidiasis. J Pharm Bioall Sci 2014;6, Suppl S1:9-12

How to cite this URL:
Dineshshankar J, Sivakumar M, Karthikeyan M, Udayakumar P, Shanmugam K T, Kesavan G. Immunology of oral candidiasis. J Pharm Bioall Sci [serial online] 2014 [cited 2019 Nov 11];6, Suppl S1:9-12. Available from: http://www.jpbsonline.org/text.asp?2014/6/5/9/137251

In a day, today life people are affected by so many systemic diseases such as diabetics, hypertension, etc., Many systemic diseases and treatment for numerous conditions can predispose the individual to many bacterial and fungal infections. Those bacteria and yeast form a complex bio layer covering the mucosal membrane of the body. Among this candidiasis is considered to be important opportunistic pathogens due to increasing frequency of this infection in compromised patient groups such as those who on cancer chemotherapy, broad-spectrum antibiotic and human immunodeficiency virus (HIV)-infected individuals. [1]

Candida albicans is a unique human parasite capable of colonizes, infect, and persist on mucosal surfaces, and stimulate mucosal immune responses. Candida may seek to induce a protective host immune response that permits its own survival. Underlying acquired immunity to the fungus is usually present in immunocompetent adults, and is presumed to prevent progression from mucosal colonization to symptomatic infection. [2] Oral health is dependent on the integrity of the mucosa, which normally prevents the penetration of microorganisms as well as macromolecules, which might be antigenic. [3] Combination of recent knowledge and increasingly sophisticated technology, the future for Candida research will doubtless be fruitful, exciting, and highly rewarding.

The mucosa is also protected by two independent immune systems

  • The systemic immune system and
  • The secretory immune system.


The oral cavity is part of the secretory or mucosal immune system which can be stimulated locally or systemically. Diseases such as candidiasis are of particular interest because potentially both the secretory and systemic immune systems may be involved in the maintenance of oral health. [3]

Host defense mechanism against Candida infection

Host defense against infections with Candida spp. depends on rapid activation of an acute inflammatory response by innate immunity, followed by an incremental stimulation of specific immune responses mediated by T-cells (cellular immunity) or B-cells (humoral immunity). The first step in initiating an immune response during infection is represented by recognition of conserved chemical structures named pathogen-associated molecular patterns (PAMPs) of the invading pathogen by pattern recognition receptor (PRRs). It is now clear that PRR engagement by PAMPs is a crucial event coordinating the succession of processes leading to pathogen elimination. In the case of Candida infection, these events start with Candida sensing, followed by phagocytosis, killing, stimulation of cytokines, and the induction of adaptive specific immune responses. Phagocytosis of Candida is mediated by the concerted action of humoral and cellular components of the immune system. The most important cells involved in the phagocytosis (and subsequent killing) of Candida are neutrophils and macrophages. In addition, macrophages together with the monocytes are the major producers of proinflammatory cytokines. These innate immune cells are important cellular components of host defense against disseminated Candida infections. Following uptake by neutrophils and mononuclear phagocytes, killing of Candida occurs through both oxidative, and nonoxidative mechanisms. [4]

Candida cells as immunogens

Once the framework in which Candida immunogens and potentially protective antigens should be placed is established, it may be easier to say that the most potent Candida immunogen is the whole Candida cell itself. [5]

Heat-inactivated cells, and even more so, a living attenuated Candida vaccine, induce in animals not colonized by C. albicans, a highly protective response against a virulent fungal challenge both in mucosal infection models and in systemic ones. The role of early involvement of natural immunity, in particular interleukin (IL)-4, IL-12, and IL-6 dependent on the activation of the protective type 1 CD4 + T-cell response has also been recently emphasized. [6]

In systemic Candida infection by parenteral challenge, the fungus disseminates through blood and lymphatics and induces a strong inflammatory response, mostly in the target organs, of which the kidney seems the principal one. The abscessual action is typical of this infection and hyphae of C. albicans are seen surrounded by polymorphonucleate cells and macrophages at the site of infection. [7]

Inflammation is the mandatory source and mediators of cytokines such as IL-6 and also tumor necrosis factor-α (TNF-α), whose critical role for induction of the protective axis natural immunity. The mechanisms of immunoregulation and effector activity, in both mucosal and systemic infections, major protective antigens have been actively sought for with only limited success. [8]

Interaction of Candida albicans with the host immune system

Innate primary defense mechanisms play key roles in preventing yeast colonization of the oral cavity.

These primary defenses include

  • The physical barrier of the epithelia
  • Lingual antimicrobial peptide, a defensin with broad-spectrum antimicrobial activity that is expressed in epithelia surrounding oral lesions
  • Secretory IgA, which aggregates yeasts and assists in clearance, and
  • Salivary factors.


Saliva flow rate affects microbial clearance, and specific salivary molecules-such as lysozyme, histatins, and lactoferrin have candidacidal properties. [9]

Phagocytes provide the second line of defense against invasive Candida infection. In the immunocompetent host, neutrophils, eosinophils, and monocytes phagocytose yeast and hyphal forms of C. albicans that gain access to deeper tissues. During acute inflammatory responses to Candida infection, neutrophils predominate numerically and in candidacidal activity. Both oxidative and nonoxidative mechanisms are involved in the intracellular killing of Candida, but these are not always effective. For maximum killing efficiency, granulocytes and macrophages require augmentation by cytokines such as interferon-gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (CSF), and IL-1 and IL-2, produced by T-cells. [10]

A significant factor in the pathogencity of C. albicans is the ability of surface molecules, such as mannoproteins and complement receptor to modulate phagocyte responses. [11]

The importance of cell-mediated immunity in resistance to Candida infection is illustrated by the severe mucosal candidiasis seen as a result of T-cell dysfunction in AIDS patients and in many people with chronic mucocutaneous candidiasis (CMC). This contrasts with neutropenic patients, who are at greater risk of disseminated infection. Humoral immunity, in the form of serum antibodies, plays a lesser role in the defense against infection. [9]

Host defense immune factors against Candida

Granulocytes

Bone marrow-derived cells, probably neutrophils, are crucial to the natural resistance to C. albicans. Individual granulocytes can phagocytose up to 10 yeast, but the proportion killed remains constant at about 20-30% regardless of the number ingested. The myeloperoxidase (MPO)-hydrogen peroxide-halide system appears to play a major role in the intracellular killing of Candida. Susceptibility to candidal and staphylococcal infection has been the chief problem resulting from MPO deficiency. Okuda et al. (1991) reported a case of alveolar pyogenic granuloma in the maxilla caused by infection with C. albicans in a patient with MPO deficiency. [12]

The candidacidal activity of human neutrophils has been shown to be enhanced independently by immune IFN-α and TNF. In the presence of sub-optimal levels of IFN-α, TNF acts synergistically to increase neutrophil effector function. Cytokines such as granulocyte CSF can increase production of neutrophils by bone marrow and increase resistance to C. albicans. Granulocytes can also kill the mycelial elements of Candida, and the capacity to bind and to generate microbicidal oxidants is augmented by serum opsonins. [13]

Cell-mediated immunity

Although phagocytosis represents the prime mechanism by which C. albicans is controlled, the intrinsic candidacidal abilities of both granulocytes and macrophages are quite limited, and full expression of their effect is dependent on augmentation by cytokines synthesized or induced by T-cells. Candida infections are consistently seen when cell-mediated immunity is depressed. Lymphokine production by T-cells is initiated by an antigen-specific interaction. This process involves antigen processing and presentation by macrophages or other accessory cells that carry appropriate (compatible) Class 1 and Class 2 major histocompatibility complex antigens on their surface. [13]

In this context, it is significant that human Candida-specific T-cells require human leukocyte antigen-DR (HLA-DR)-compatible macrophages for their activation, and that Candida infection markedly increases the expression of HLA-DR and HLA-DQ antigens on the surface membranes of epithelial cells. [14]

Activation of T-cells produces a wide range of lymphokines that can, in turn, modulate the functions of macrophages and other leukocytes. IFN-γ is the only lymphokine known to increase the microbicidal activities of macrophages: it also initiates TNF synthesis by them. In the presence of suboptimal levels of IFN-γ, Candida killing by neutrophils is markedly enhanced by TNF. Unfortunately, the cytokines produced as a result of T-cell/macrophage interactions have the potential to exacerbate symptoms of illness as well as enhancing clearance of the infection. [13]

Polysaccharide antigens of C. albicans may generate a complex series of interactions that suppress both T- and B-cell responses. These effects may eventually block the synthesis of both IL-2 and IFN-γ, as well as the expression of the Tac antigen (the IL-2 receptor) by normal T-cells; antigen presentation and IL-1 production by monocytes may also be affected. [15]

Humoral immunity

Serum antibodies can affect the growth of C. albicans. The major specific immunologic factor in saliva is sIgA, which may be a primary defense against oral candidiasis by aggregating the organisms and by preventing their adherence to mucosal epithelium. [16]

Humoral and cell-mediated immunity to C. albicans may comprise a second line of defense when penetration of mucosa or systemic infection occurs. Both mucocutaneous and systemic candidiasis are typically associated with defects in the cell-mediated immune response. These can be caused by deliberate immunosuppression (as in transplant patients) or in cancer patients treated with cytotoxic drugs; they can be associated with some underlying disease, such as the HIV infection, or they may reflect specific deficiencies in the cell-mediated immune response, as in CMC. [13]

Immunological aspect of candidiasis

As far as specific immunity against oral candidiasis is concerned, both secretory IgA and cellular immunity might play a role in the protection of the oral mucosal surfaces against candidal infection. Indeed, a markedly increased prevalence of candidal infection can be seen in IgA-deficient individuals. Among patients with CMC, which is a systemic disease with widespread chronic hyperplastic candidiasis lesions, over 50% appear to have reduced IgA antibodies. [17]

In CMC, a wide spectrum of immune abnormalities has been reported, and these range from lowered serum lgM and IgG antibodies to defects in lymphocyte transformation and mitogen stimulation in the most severe types of CMC. It is not clear, however, whether these immune defects are primarily due to the disease or a consequence of it. A number of studies have shown restoration of immune functions once Candida has been cleared by antifungal therapy. There is considerable evidence to suggest that cell-mediated immune response is impaired in patients with CMC. [3]

It has been suggested that patients with CMC can be characterized into four groups

  • Group 1 who have depressed delayed hypersensitivity (DH) abnormal macrophage migration inhibition factor (MIF) but normal lymphocyte proliferative response to Candida (lymphozytentransformations test [LTT]).
  • Group 2 with no DH but normal MIF and LTT
  • Group 3 with defects in all three cellular response and possibly in neutrophil chemotaxis also
  • Group 4 with especially normal response.


As far as detected, humoral response were normal in all the groups. [3]

Budtz-Jörgensen demonstrated the role of cellular immunity in resisting chronic candidal infections in the rhesus monkey. Evidence for the significant role played by cellular immunity against Candida infection can be found in the observation that infection by the fungus is a widespread problem among patients with severe T-cell defects and not in those with B-cell defects, unless the latter also have concomitant T-cell defects. [18]

Williams et al., who characterized the inflammatory cell infiltrate in CHC using immunocytochemical techniques, concluded, on the basis of their finding that mucosal defense against Candida infection involves a cell-mediated reaction. This consists of recruitment of macrophages and local production of immunoglobulin with a prominent IgA component. [19]

Candida appears to vary between patients with different types of candidiasis. In some studies, it was shown that antibody titers in chronic hyperplastic candidiasis patients were not as high as in patients with Candida-associated denture stomatitis. It had been suggested that this observation perhaps reflects the greater mucosal area involved in the latter condition with the concurrent transmucosal penetration of antigens compared with most cases of chronic hyperplastic candidiasis. [17]


   Conclusion Top


Although considerable progress has been made in the understanding of Candida and oral candidiasis during the last few decades, much remains to be done. Understanding the pathogenesis of fungal diseases from the perspectives of immunology, it is hoped that this knowledge will help direct the development of future therapeutics and minimize risk of disease in the ever-increasing population of immunocompromised patients seen in day today practice.

 
   References Top

1.Jin Y, Samaranayake LP, Samaranayake Y, Yip HK. Biofilm formation of Candida albicans is variably affected by saliva and dietary sugars. Arch Oral Biol 2004;49:789-98.  Back to cited text no. 1
    
2.Netea MG, Maródi L. Innate immune mechanisms for recognition and uptake of Candida species. Trends Immunol 2010;31:346-53.  Back to cited text no. 2
    
3.Chaffin WL, Lopez-Ribot IL, Casanova M, Gozalbo D, Martinez IP. Cell wall and secreted proteins of Candida albicans: Identification, function and expression. Microbiol Mol Biol Rev 1998;62:130-80.  Back to cited text no. 3
    
4.Cassone A, De Bernardis F, Torosantucci A. An outline of the role of anti-Candida antibodies within the context of passive immunization and protection from candidiasis. Curr Mol Med 2005;5:377-82.  Back to cited text no. 4
    
5.Dangi YS, Soni ML, Namdeo KP. Oral candidiasis: A review. Int J Pharm Pharm Sci 2010;2:23-8.  Back to cited text no. 5
    
6.Mencacci A, Del Sero G, Cenci E, d'Ostiani CF, Bacci A, Montagnoli C, et al. Endogenous interleukin 4 is required for development of protective CD4+T helper type 1 cell responses to Candida albicans. J Exp Med 1998;187:307-17.  Back to cited text no. 6
    
7.Romani L, Bistoni F, Mencacci A, Cenci E, Spaccapelo R, Puccetti P. IL12 in Candida albicans infections. Res Immunol 1995;146:532-8.  Back to cited text no. 7
    
8.Sitheeque MA, Samaranayake LP. Chronic hyperplastic candidosis/candidiasis (candidal leukoplakia). Crit Rev Oral Biol Med 2003;14:253-67.  Back to cited text no. 8
    
9.McCullough MJ, Ross BC, Reade PC. Candida albicans: A review of its history, taxonomy, epidemiology, virulence attributes, and methods of strain differentiation. Int J Oral Maxillofac Surg 1996;25:136-44.  Back to cited text no. 9
    
10.Greenfield RA. Host defense system interactions with Candida. J Med Vet Mycol 1992;30:89-104.  Back to cited text no. 10
    
11.Lynch DP, Gibson DK. The use of Calcofluor white in the histopathologic diagnosis of oral candidiasis. Oral Surg Oral Med Oral Pathol 1987;63:698-703.  Back to cited text no. 11
    
12.Lehrer RI, Cline MJ. Leukocyte myeloperoxidase deficiency and disseminated candidiasis: The role of myeloperoxidase in resistance to Candida infection. J Clin Invest 1969;48:1478-88.  Back to cited text no. 12
    
13.Scully C, El-Kabir M, Samaranayake LP. Candida and oral candidiasis: A review. Crit Rev Oral Biol Med 1994;5:125-35.  Back to cited text no. 13
    
14.Jontell M, Scheynius A, Ohman SC, Magnusson B. Expression of Class II transplantation antigens by epithelial cells in oral candidosis, oral lichen planus and gingivitis. J Oral Pathol 1986;15:484-8.  Back to cited text no. 14
    
15.Lombardi G, Vismara D, Piccolella E, Colizzi V, Asherson GL. A non-specific inhibitor produced by Candida albicans activated T cells impairs cell proliferation by inhibiting interleukin-1 production. Clin Exp Immunol 1985;60:303-10.  Back to cited text no. 15
    
16.Epstein JB, Kimura LH, Menard TW, Truelove EL, Pearsall NN. Effects of specific antibodies on the interaction between the fungus Candida albicans and human oral mucosa. Arch Oral Biol 1982;27:469-74.  Back to cited text no. 16
    
17.Akpan A, Morgan R. Oral candidiasis. Postgrad Med J 2002;78:455-9.  Back to cited text no. 17
    
18.Budtz-Jörgensen E. Immune response to C. albicans in monkeys with experimental candidiasis in the palate. Scand J Dent Res 1973;81:360-71.  Back to cited text no. 18
    
19.Williams DW, Potts AJ, Wilson MJ, Matthews JB, Lewis MA. Characterisation of the inflammatory cell infiltrate in chronic hyperplastic candidosis of the oral mucosa. J Oral Pathol Med 1997;26:83-9.  Back to cited text no. 19
    



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