Oral bio exam 3

primary oral disease are caused by:

infectious oral microorganisms

oral microorganisms (3)

Bacterial, viral, and fungal etiology

autoimmune diseases with oral manifestations

• Sjorgren’s syndrome and pemphigus

• recurrent oral mucosal ulcers

Bacterial etiology

• Dental caries

• periodontitis

Viral etiology

• herpes simplex type I

• HPV

• Epstein bar virus

Fungal etiology

• Oral candidiasis

• caused by acquired immunodeficiency, poor OH, prolonged antibiotic use

immune mechanisms of oral cavity derive from: (2)

• secretory system (secretions of major/minor salivary glands)

• systemic immune system (gingival reticular fluid)

oral cavity immune barriers: (4)

• saliva and mucins

• lymphoid tissue (tonsils) (major site of oral cavity manifesting bacterial infections)

• oral mucosal lining

• periodontium (including gingival crevice)

Fluid barrier defense

Saliva

mechanical barrier defense

epithelium and connective tissue

chemotactic defense

neutrophils, lymphocytes, cytokines

innate vs adaptive immune responses

Oral adaptive immunity:

• lymphocytes, T and B cells

• in underlying connective tissue

• B cell products can transudate to gingival crevice

Oral innate immunity:

• secreted by salivary glands, epithelial cells and leukocytes

• they kill, and inhibit growth of microorganisms

• have broad spread antibacterial, antifungal, and antiviral properties

periodontal disease involves:

• dysbiosis of microbiome

• activate complement system and vasodilation

• chemotactic recruitment of inflammatory exudate (mostly neutrophils)

• adaptive immunity brings in T and B cells (for antibodies and cytokines)

Acquired Ig factors

secretory IgA, IgG, IgM

Non-Ig, innate factors

lysozyme, lactoferrin, peroxidase, agglutinins, phagocytic cells

Saliva

• key role in innate host defense

• lysozyme=cleaves bacterial cell walls

• antimicrobial peptides(histatins) inhibit growth of caries causing bacteria

Salivary IgA (S-IgA)

• aggregates oral bacteria like S. mutans to prevent plaque formation

• Ab of IgA control microbial adherence to musical surfaces

Most important humoral mediator of specific oral mucosal immunity

secretory IgA

S-IgA Antibodies

bind to specific microbial targets and control microbial adherence to mucosal surfaces or neutralize toxins

Secretory IgA

major Ab in saliva, inhibits adherence and agglutinates bacteria

lactoferrin

bacteriostatic-iron binding

lysozyme

destroys the outer membrane of bacteria (against S. mutans)

Agglutinins

glycoproteins, histatins, PLPs

Oral mucosal immune system components (3)

Phagocytes, antigen-presenting cells, lymphocytes

pharyngeal Waldeyer’s ring

a central mucosal inductive site there Ag are processed by APCs

Antigens stimulate:

Naive musocal B and T cells

Tonsils

• site of systemic (pharyngeal) bacterial infection, because of clefts that can collect debris (tonsilitis)

Waldeyer’s ring components (4)

• palantine tonsils (sides of back of mouth, we can see)

• lingual tonsils (at base of tongue)

• tubal tonsils (near opening of auditory tubes)

• pharyngeal tonsils (adenoids, in upper throat behind nose)

How tonsils support immunity

• tonsils and adenoids are inductive sites where immune response begins

• they activate B cells that develop into plasma cells to make Ab

• leads to IgA production (in saliva to protect mucosal surfaces)

connective tissue of periodontium

are highly vascular=facilitate vascular leukocyte emigration in response to infection

Gingival crevicular fluid (GCF)

• bathes the gingival sulcus

• carries complement components and Ab, neutrophils, and plasma cells (to prevent tissue invasion)

Periodontium

supports and surrounds the teeth, is susceptible to acute and chronic inflammation from plaque bacteria in gingival sulcus

Subgingival biofilm

• present in the gingival crevice

• elicits host response to control bacteria

• neutrophils are recruited, TLRs on gingival epithelium, then produce antimicrobial peptides

immunocompromised patient

acquired condition from: HIV/AIDS, cancer chemo therapies, or prolonged use of corticosteroids

HIV immunodeficiency

low levels of CD4+ T cells (higher susceptibility to candida albicans)

common oral manifestations

xerostomia, aphthous ulcers, recurrent fungal and viral infections

oral apthous ulcers

• etiology is unclear

• risk factors: stress, UV light, malnutrition, genetics

• appear in buccal and lingual mucosa, very painful

an oral apthous ulcer

autoimmune disease affecting the oral cavity

• can be inflammatory disease with oral manifestations

• etiology can be multifactorial

• can have auto Ab with unknown causes

autoimmune disease examples

• Sjogrens disease

• rheumatoid arthritis

• systemic lupus

• pemphigus vulgaris

autoimmune disease oral manifestations

• apthous ulcers

• desquamative gingivitis

• xerostomia

• increased caries risk

• MOST COMMOM= MUCOSAL ULCERATIONS

mucosal ulceration cause

autoantibodies attack keratinocytes, cell junctions, and desmosomes

pharmacologic agents to treat autoimmune diseases

• immunosuppressants

• glucocorticoids

• nonsteroidal anti-inflammatory medications (NSAIDs)

oral manifestations of diseases affecting oral region

TNF alpha inhibition

• a target for autoimmune disease treatment

• increases liability to infections

immunosuppressive drug used to:

• reduce immune response against transplanted organs

• treat autoimmune diseases (like pemphigus, lupus, or allergies)

Glucocorticoids

• large doses over prolonged periods of time—>poor wound healing response and decreased resistance to infection

• mainly given as topical for ulcers

NSAIDs

• used for pain because of its analgesic, antipyretic, and anti-inflammatory effects

• block prostaglandin by inhibits COX1 and COX2

• adverse effects: increased bleeding risk and renal toxicity

Salicylates

• like aspirin

• irreversibly inhibits COX2

• has antiplatelet effects to inhibit Thromboxane A2 production, and inhibit NF-kappa B (inflammation TF)

• adverse effects: GI bleeding

most common oral cancer

oral squamous cell carcinoma (OSCC)

OSCC risk factors

smoking and chronic alcohol consumption

OSCC common locations

• lateral borders of tongue and floor of mouth

• important to do thorough oral cancer screening on all patients

Salivary biomarkers

• elevated salivary and serum levels of Copper, zinc, and iron=oral malignancy likely

• salivary albumin, salivary lactate dehydrogenase, and oxidative stress are other markers

Pro-inflammatory cytokines

• like IL-6 and IL-8

• significantly increased in serum and saliva of patients with leukoplakia and OSCC

Activation of classic complement pathway

• CD4 containing split fragments

• a propose biomarker for OSCC

apoptotic cells

• another potential marker for oral cancer

• significantly fewer apoptotic epithelial cells in oral cancer

Immunostimulators are prescribed:

to enhance the immune response against infectious diseases, tumors, and immunodeficiency disorders

Dental caries vaccines

• conventionally available vaccines taken before disease development, immunization follows eruption of baby teeth

• early immunization can have benefits for adult teeth as well

• local passive immunization is better (because there are various antibodies against S. mutans Ag)

tooth decay is:

multifactorial

dental vaccine adverse effect:

human heart reactivity

vaccination trials conducted in 3 phases:

• infants

• preschool children

• preadolescent children

primary immunodeficiencies

• congenital

• inherited/genetic defects or congenital (development error)

• IgA deficiency is the most common

secondary immunodeficiencies

• acquired

• associated with: infections, aging, malignancies, therapy (iatrogenic)

Lymphoid deficiencies

• combined immunodeficiencies

• B and T cells affected

  • T cell deficiencies: depend on defect, commonly see decreases in overall Ig levels

  • B cell deficiencies: lack of one to lack of all isotypes, pts often have recurrent bacterial infections

Myeloid deficiencies

Phagocytosis issues, usually see increased bacterial infections

Severe combined immunodeficiency (SCID)

• all have defect in T-cell compartment (can affect B and NK cells)

• low number of circulating lymphocytes

• several recurrent infections (fatal early in life), fungal or viral infections

• treat with bone marrow transplant

SCID examples (2)

• X-linked severe combined immunodeficiency

• Autosomal mutants

X-linked severe combined immunodeficiency

• defect in gamma-chain of IL-2 receptor

• lymphocyte development is abnormal

autosomal mutants

• defect in RAG1, RAG2 that prevent normal development of B and T cells

• defect in adenosine deaminase (ADA= important in DNA synthesis

Di George Syndrome (T cell defect)

• congenital thymic aplasia/hypoplasia

• defect in fetal development during week 6-10

• unknown cause

• treat with: thymic graft from fetus (13-14th week)

  • thymic graft usually doesn’t show GvHD

4 B cell defects

• x-linked hypogammaglobulinemia

• severe B cell deficiency

• x-linked hyper IgM immunodeficiency

• Selective deficiencies in Ig classes

X-linked hypogammaglobulinemia

• aka Bruton

• defective B-cell tyrosine gene

• rearrange H chain, but not L chain

• essentially no peripheral B cells

Severe B cell deficiency

• all Ig levels are low

• recurrent bacterial infections

• treat with: passive immunoglobulins

• pts rarely survive past teen years

X-linked hyper IgM immunodeficiency

• defect in class switch and CD40L on T cells

• see high IgM and low IgG and IgA levels

selective deficiencies in Ig classes

• IgA is the most common

• pts can be asymptomatic or have recurrent respiratory infections

• defect is: outside the Ig genes

Myeloid immunodeficiencies

• chronic granulomatous disease (CGD)

Chronic granulomatous disease (CGD)

• defects in oxidative burst in phagocytic cells

• lack of NADPH oxidase activity (less ROS products)

• results in phagocytic difficulty in killing microbes

• symptoms: recurrent bacterial and fungal infections, excessive inflammation

• mostly X-linked

HIV/AIDS (secondary immunodeficiency)

• HIV primarily infects CD4+ T cells (lack of Th binding to CD4 protein)

• as CD4+ T cell count lowers, more opportunistic infections occur

• AIDS=HIV positive with CD4 cell count <200/uL blood

HIV/AIDS CD4 cell count over the course of infection

Cancer cells are

‘altered self‘ cells

Cancer cell properties

• may express different markers from early development

• abnormal growth control (lack of apoptosis and p53 mutations)

• increased telomerase expression

• can move to other locations (malignant=dangerous)

Malignant, invasion, and metastasis of cancer cells

malignant= cancerous tumor

metastasis= cancer spread to distant site

invasion= cancer spread to nearby site

Cancer causing mutation (3)

• Chemical carcinogens: nitrates, asbestos, nicotine, tar

• physical carcinogens: UV light, radiation

• Viruses: Human T cell lymphotropic virus I, HPV

Cancer properties as a result of mutations

• complex genetic disease (multi-step to originate)

• heterogeneous (constant changes and evasion of host control)

• lack of antigenicity (from host)

• metastatic (can move form one location to another)

Immune system role in cancer

• Variable

• cancer is host derived, tumor may not be recognized as foreign

• in immunosuppressed, higher incidence of cancer (ex: elderly, AIDS pts)

• tumor infiltrating lymphocytes (TILs)

3 methods to detect/monitor tumors

• radioimmunoassay

• immunoelectrophoretic

• ELISA of secretions/sera/urine

Monitoring/detecting tumors is best for:

• myeloma proteins (B cell tumors)

• oncofetal antigens (CEA, AFP)

• prostate specific antigen (PSA)- expressed higher in prostate cancers

5 types of immuniological assays

• radioimmunoassay (RIA)

• agglutination

• ELISA

• immunofluorescence

• western blot

Radioimmunoassay (RIA)

• measures serum antigen levels (hormones)

• in type I hypersensitivity reactions

Agglutination

clumping of cells (ABO blood typing)

ELISA

• detect present of tumor antigens

• enzyme linked immunosorbent assay

• detects antigen levels in serum (w/o radioactivity)

immunofluorescence

• monitor certain tumor markers on cells in blood flow or in situ

Western blot

antibodies bind to protein (ex: anti-HIV Ab)

Detection of minimal disease

• PCR: detect cancer genes within cells

• changed in cytokine levels: tumor antigens (ELISA/RIA)

conventional cancer therapy

reduce cancer cell numbers with surgery, radiotherapy, chemotherapy

passive immunotherapy

• monoclonal antibodies added to tumor specific antigens to stimulate ADCC or C’ activation

• monoclonal antibodies also:

  • signal apoptosis

  • prevent angiogenesis (prevent new blood vessels)

  • stimulate immune response

SLAMF7

• multiple myeloma

• activated NK cell mediated tumor killing