PERIODONTAL PATHOGENESIS,

IMMUNITY and AUTOIMMUNE DISEASES

By Dr. Stephen B. Weinmann

Microorganisms Associated with Various

Forms of Periodontal Disease

HEALTH

1) Actinomyces Naeslundii

2) Actinomyces Viscosus

3) Rothia Dentocariosa

4) Veillonella Parvula

5) Streptococcus Uberis

6) Streptococcus Sanguis

7) Streptococcus Mitis

Experimental Gingivitis (supragingival)

1) Actinomyces Israelii

2) Actinomyces Viscosus

Experimental Gingivitis (subgingival) ANUG

Bacteroides

1) Actinomyces Viscosus Intermedius or

2) Actinomyces Naeslundii Prevotella

3) Fusobacterium Nucleatum intermedia

4) Streptococcus Auginosus

5) Lactobacillus Sp.

6) Treponema Sp.

7) Veillonella Parvula [1]

Localized Juvenile

Periodontitis

Actinobacillus

Actinomycetem-

comitans

Bacteroides

Intermedius or

Chronic Gingivitis Prevotella

Intermedia

1) Actinomyces Israelii Capnocytophaga

2) Actinomyces Naeslundii Ochracea

3) Actinomyces Viscosus Eikinella

4) Bacteroides Intermedius Corrodens

5) Campylobacter Sputorum

6) Capnocytophaga Gingivalis

7) Capnocytophaga Ochracea

8) Fusobacterium Nucleatum

9) Streptococcus Sanguis

10) Streptococcus Uberis

11) Veillonella Parvula

[2]

Adult Periodontitis

1) Bacteroides Capillus

2) Bacteroides Forsythus

3) Bacteroides Gingivalis

4) Bacteroides Intermedius or Prevotella Intermedia

5) Eikinella Corrodens

6) Eubacterium Brachy

7) Eubacterium Nodatum

8) Eubacterium Timidum

9) Fusobacterium Nucleatum

10) Lactobacillus Minitus

11) Selenomonas Sputigena

12)Streptococcus Intermedius

13) Wolinella Recta or Campylobacter Rectus

A source of microorganisms (reservoir) Infectious disease; and, infection

connotes the occurrence of colonization accompanied by an immune response.1

Potential pathogens can be transferred by direct (insects, animals, people),

Or indirect paths (water, soil).

Periodontal Diseases are produced by endogenous organisms derived from

exogenous organisms may be comprised of one or many clonal types.

[3]

Putative periodontal pathogens are genetically heterogeneous and consist of

many clonal types. 1

A common genotyping is restriction endonuclease analysis (REA), which is a

method of DNA fingerprinting for a bacterial species using enzymes to cleave

genomic DNA between specific sequences of nucleotide base pairs.

These fragments are separated by gel electrophoresis & stained with ethidium

bromide resulting in a banding pattern representing the DNA fingerprint using

laser densitometry.1

The potential exists that infection may be spread by dental instruments from one

site to another within the oral cavity; such as, Streptococcus Mutans,

Actinobacillus Actinomycetemcomitans. Periodontal probes even transfer

pathogens from diseased to healthy sites.

Spouses may be at risk for being colonized by pathogens if the mate is infected;

but the chances are low. 1-4

If a child harbors a pathogen, at least one of the parents will usually exhibit the

same genotype of bacteria. Transmission of pathogens is more common than

previously thought. But, between siblings is difficult to verify. 1

Animals can be sources of bacterial transfer.

Saliva is a major vector for bacterial transfer. 11

[4]

Contagious leads one to think in terms that pathogens are easily communicable

and easily induce disease.

Specific subgingival bacteria are the primary risk factor for developing disease.1

Most Periodontal Disease is due to microorganisms. The primary defense

mechanism against these microorganisms is the epithelial attachment. The

epithelial attachment has two layers (the Stratum Germinativum & the Stratum

Spinosum); and, the epithelial attachment adheres cell to cell. There is no

organic attachment as advocated by Dr. B. Orban; however, there is a cementing

attachment which binds one cell to another. This cementing attachment is

believed to be a protein-linked polysaccharide that is a sticky, mucilaginous

substance that helps neighboring cells to adhere to each other. Certain drugs,

such as Cortisone, the integrity of the cementing substance and a in the

production of epithelial cells hyperplasia. As the intercellular cementing

substance breaks down a “splitting” of the cells occurs; and, the epithelial cells

proliferate & migrate. Once “splitting” of the epithelial structure occurs the

collagen fibers & the ground substance become adversely effected.

Of the more than 250 bacterial species that may colonize the gingival crevice in

humans, only 10 or so appear to be involved in periodontal disease. According to

Clark & Loe they are as follows: 5

[5]

1) Actinobacillus Actinomycetemcomitans, 2) Treponema Denticola, 3)

Eikinella Corrodens, 4) Bacteroides Gracilis, 5) Eubacterium species, 6)

Wolinella Recta, 7) Capnocytophaga species, 8) Prevotella Intermedia, & 9)

Black-pigmented Bacteroides species including Porphyromonas Gingivalis.

When host cell membranes are injured a process called the ARACHIDONIC

ACID CASCADE 7,8 results. The biologically active products in this cascade are

Leukotrienes, Prostaglandins, Thromboxane, and other products. The effects are

the attraction of phagocytic cells and enhanced vascular permeability; allowing

the influx of serum factors (antibodies & complement) destruction of localized

microorganisms and the potentially toxic products of microbial metabolism.

There are potentially harmful effects to the periodontal tissues that cause

mucosal edema, bone resorption, and collagenase (digests connective tissue

fibers) creating part of the periodontal pathology. The primary phagocytic cells 6-10

derived from the Leukotrienes are polymorphonuclear neutrophils (PMNs) and

macrophages. The PMNs make up 50-70% of the circulating leukocytes and

originate in the bone marrow from pluripotential stem cells induced to

differentiate by colony-stimulating factors (CSFs).

[6]

There are three phases of microbial attack by neutrophils (1) chemotaxis

(directed movement of an attractant substance toward a target organism), (2)

phagocytosis (engulfment of the microbe), and (3) microbial killing (a chemical

attack on the ingested microorganisms by bactericidal proteins,

myeloperoxidase, and cathepsins and the formation of oxygen-free radicals

(superoxide & hydroxyl ion). Chemotaxis 6-10 involves the margination of

circulating neutrophils along the endothelial lining of the postcapillary venules,

their penetration through the vascular wall, and their directed migration toward

the extravascular source of the infection. The initial adhesion of neutrophils to the

vascular endothelium is mediated by surface glycoproteins (CD11/CD18), which

bind to adhesion molecules on activated endothelium (ICAM-1, ELAM-1).

Leukocyte proteases are responsible for the production of complement-derived

chemotaxins. The serum-complement system is composed of more than twenty

serum proteins which when activated have potent biological effects. There are 2

main pathways that the proteins of the complement system are activated. These

are the classical pathway (binding of antibody to bacterial cell wall surfaces)

and the alternate pathway (activated by endotoxins of certain gram- bacteria).

Meanwhile, lipoxygenases mediate production of arachidonic acid-derived

leukotrienes & hydroxyacids.

[7]

OPSONIMS 7-10 (proteins that coat microorganisms & promote their avid uptake

by neutrophils) is made up of complement fragment C3b, fibronectin (a large

plasma protein), and immunoglobulins. These substances adhere to

microorganisms & promote binding to C3b & Fc receptors on the neutrophils

plasma membrane. The microbial activity of neutrophils involves two interacting

functions: degranulation and activation of the respiratory burst.

NEUTROPHILS 6-10 (polymorphonuclear leukocytes or PMNs) have two sets of

cytoplasmic granules. The azurophilic granules contain acid hydrolases,

lysozyme, neutral proteases(Cathepsin G & Elastase), myeloperoxidase, & basic

proteins. Specific granules contain lysozyme, transcobalamin III, apolactoferrin,

collagenase, & The C5 cleaving protease which aid in the digestion of the

bacterial cell wall, degrade cellular debris, dissolve connective tissue, and bind

substances like iron that are useful in bacterial metabolism. Neutrophils are the

circulating white cells needed for phagocytosis and proteolysis by which bacteria,

cellular debris, and solid particles are destroyed and removed. They are the

primary effector cells of the acute inflammatory response & contain potent

antibacterial peptides called defensins. Neutrophils posses receptors for the

metabolites of the complement molecule C3, complement receptors CR1, CR3,

CR4, C5, C5aR, and the IgG antibody (FcR) that enable neutrophils to participate

in phagocytosis.

[8]

MAST CELLS 6-10,12,13 are a constituent of connective tissue containing large

basophilic granules that contain Serotonin, heparin, histamine, & bradykinin all of

which are released from the mast cell in response to injury & infection. Histamine

causes blood vessels to dilate and become more permeable allowing an influx of

serum & serum factors into local tissue spaces. Serotonin is a naturally occurring

derivative of tryptophan found in platelets and is released upon injury to blood

vessel walls. It acts as a vasoconstrictor. Heparin is a naturally occurring

mucopolysaccharide that acts as an antithrombin factor preventing intravascular

clotting. It is found mostly around connective tissue surrounding capillaries.

Bradykinin is a peptide of nonprotein origin comprised of 9 amino acid residues

produced from 2-globulin by kallikrein and acts as a potent vasodilator.

Bradykinins and other kinins both directly & indirectly affect the renal secretion of

salt and water. Mast cells 14-16 possess receptors for C3a, C5a, and the antibody

molecules IgE (FcR) and IgG (FcR). Mast cells can synthesize other

inflammatory mediators such as SRS-A, TNF-, and leukotriene C4.

The IMMUNE SYSTEM 6-10 is a network of interacting cellular & soluble

components. Its function is to distinguish entities within the body as “self” or

“nonself” and to eliminate those that are “nonself”. Microorganisms are the

primary “nonself” entities, but neoplasms, transplants, foreign substances, &

implants are also important.

[9]

Two mechanisms enable the immune system to function: (1) NONSPECIFIC

(innate) IMMUNITY and (2) the SPECIFIC (adaptive) IMMUNITY. Nonspecific

immunity is present at birth, does not develop memory, & needs no previous

encounter with the offending substance. The cellular components are (1) the

phagocytic system whose function is to ingest / digest invading microorganisms,

and (2) Natural Killer (NK) cells whose function is to kill some tumors,

microorganisms, and virally infected cells. NK cells possess Killer Inhibitory

Receptors (KIR) and Killer Activating Receptors (KAR). Phagocytes include

neutrophils, monocytes, & macrophages. CYTOKINES are nonimmunoglobulin

polypeptides secreted by monocytes & lymphocytes in response to interaction a

nonspecific antigen (Ag), a specific antigen (Ag), or a nonspecific soluble

stimulus (endotoxins, other cytokines). Cytokines affect the magnitude of

inflammatory or immune responses. Specific (adaptive) Immunity has the ability

to learn, to adapt, and memory. The cellular component is the lymphocyte; the

soluble components are the immunoglobulins (Igs). The lymphocytes are divided

into two subsets: (1) the T- lymphocytes (Thymus- derived), & (2) the B-

lymphocytes (bone marrow derived). The T- lymphocyte is responsible cellular

immune responses and acts in rejection of graft tissues & organ transplants, the

production of lymphokines such as (1) osteoclast-activating factor [OAF] that has

the ability to cause bone resorption;

[10]

(2) Macrophage migration inhibitory factor (MIF) which the migration of

Macrophages Phagocytic efficiency; (3) chemo-attractiveness for phagocytic

cells, (4) toxicity for fibroblast cells; and, (5) protection of host cells from viral

infections. Another important function of T cells is called “helper T cell” which

promotes the immune response of other lymphocytes to foreign antigens by

releasing soluble proteins called helper factors. It is the subpopulation of “helper”

T-cells that are affected by the Human Immunodeficiency Virus (HIV). The T cell

induces B-cell activation. CD4 and CD8 are T-cell coreceptors.

Immunosuppressants block the intracellular processes of T-cell activation. Both

Cyclosporin A and Tacrolimus bind and activate immunophilins causing their

immunosuppressive effects.

The B-lymphocyte is responsible for the humoral immune response. It originates

in bone marrow; and, is a precursor of the plasma cell which release antibodies

and memory cells that provide a rapid response if the same antigen is

encountered again. Since factors involved in hypersensitivity reactions (i.e.

Calciphylaxis, activated compliment factors) have been observed in periodontal

tissues and in the crevicular fluids and may play a role in the pathogenesis of

periodontal disease. Defense mechanisms are constantly active in moderating

the effects of bacteria & their products upon the threat to periodontal health.

[11]

CYTOKINES 6-10 are divided into several groups as follows: (1) interleukins (IL),

(2) interferons (IFN), (3) tumor necrosis factors (TNF), (4) colony-stimulating

factors (CSF), (5) transforming growth factors (TGF), and (6) chemokines. A brief

discussion will be entered into here since they are discussed in detail elsewhere.

They activate oxidative metabolism.

INTERLEUKINS are a large group of cytokines produced mainly by T cells. Most

interleukins influence other cells to divide & differentiate. They are grouped as

interleukin-1 (IL-1) through interleukins-18 (IL-18).

INTERFERONS are a natural cellular protein formed when cells are exposed to a

virus or another foreign particle of nucleic acid. They induce the production of

translation inhibitory protein (TIP) in noninfected cells. TIP blocks translation of

viral ribonucleic acid giving other cells protection against the original & other

viruses. Interferon is species specific. They are listed as IFN- , IFN- , and IFN-

; or, as Interferon alpha-2a, recombinant; Interferon alpha-2b, recombinant; &

Interferon beta-1a.

TUMOR NECROSING FACTOR (TNF) is a natural body protein & can be

synthetically produced possessing anticancer properties. Adverse effects are

shock & cachexia. They are listed as TNF- and TNF- .

COLONY-STIMULATING FACTORS (CSF) is important for cells to be able to

pass a restriction point in their reproductive cycle. After cells have entered the

deoxyribonucleic acid synthesis phase it is no longer needed. They are listed as

(1) GM-CSF, (2) G-CSF, and (3) M-CSF.

[13]

TRANSFORMING GROWTH FACTOR (TGF) is a group of proteins produced by

the cells of a tumor that cause a disorderly increase in the number of cells. TGF-

induces angiogenesis, keratinocyte proliferation, bone resorption, and tumor

growth. TGF- induces fibroblast proliferation, synthesis of collagen &

fibronectin, enhances angiogenesis & wound healing, and inhibits CTL (cytotoxic

T lymphocytes), NK (natural killer), LAK (lymphokines-activated killers), and T &

B CELL proliferation.

CHEMOKINES are a new family of cytokines. They induce chemotaxis and

migration of leukocyte subsets. They are called (1) C, (2) C-C, (3) C-X-C, &

C-X3-C. Their major effects are: C--- induces chemotaxis of T & NK cells; C-C---

induces chemotaxis of T & NK cells, basophils, & eosinophils; C-X-C induces

chemotaxis of T cells, mast cells, monocytes, and eosinophils;

C-X3-C has not been well clarified at this point. Some of the receptors on

chemokines may serve as coreceptors for entry of HIV into

monocytes/macrophages.

[14]

COMPLEMENT PATHWAYS 8

Classical Pathway

Antigen-antibody Activation

complexes (C1, C4, C2)

{C1/NH, C4BP, /}

MBL pathway

Carbohydrates Activation (MBL, C3 Terminal pathway

MASP-1, MASP-2) Cleavage (C3, C5- C9) lysis

{CD59, HRF}

Alternative Pathway

Natural substances Activation

(eg, yeast walls, (C3b, B, P, D)

rabbit RBCs ) {H, 1}

(The Merck Manual, 17th Ed, 1999)

[15]

COMPLEMENT DISORDERS 8

C1q deficiency ----------------------------- combined immunodeficiency,

SLE-like syndrome

C1rs----- -----------------------------

C1s------ ----------------------------- SLE-like syndrome, glomeru-

C4------- ----------------------------- lonephritis

C2------- ------------------------------

C3------- (ACD) ------------------------------- Pyogenic infections

C5------- -------------------------------

C6------- -------------------------------

C7------- ------------------------------- Neisserial infections

C8------- -------------------------------

C9------- ------------------------------- none proven

C1 inhibitor deficiency------------- angioedema, SLE

Factor 1 (C3b inactivator) deficiency (ACD) ------pyogenic infections

Factor H deficiency (ACD) --------- hemolytic-uremic syndrome,

Glomerulonephritis

Factor D deficiency (ACD) -------- Pyogenic infections

Properdin deficiency (XL) --------- Neisserial infections

[16]

IMMUNODEFICIENCY DISEASES

DISORDERS with INCREASED SUSCEPTIBILITY to UNUSUAL

INFECTIONS:

8-10, 17

1) Primary Immunodeficiencies 2) Foreign Bodies

X- linked agammaglobulinemia Central venous catheter

DiGeorge anomaly Ventricular shunts

Chronic granulomatous disease Artificial heart valves

C3 deficiency Urinary catheter

Aspirated foreign bodies

3) Unusual Microbiological Factors 4) Obstructive Disorders

Chronic infections Bronchial asthma

Continuous reinfection Allergic rhinitis

Antibiotic overgrowth Cystic fibrosis

Contaminated water supply Urethral stenosis

Contaminated inhalation equipment Bronchiectasis

Blocked Eustachian

Tube

5) Circulatory & Systemic Disorders 6) Integumentary defects

Diabetes Mellitus Burns

Sickle Cell Disease Skull fractures

Nephrosis Midline sinus tracts

Varicose veins Ciliary abnormalities

[17]

(Circulatory & Systemic Disorders—cont.) (Integumentary defects)

Congenital Cardiac Disease Eczema

7) Secondary Immunodeficiencies

Lymphoma

Splenectomy

Immunosuppressive therapy

Chronic viral diseases

Malnutrition

Prematurity

Uremia

Protein-losing enteropathy

PRIMARY IMMUNODEFICIENCY DISORDERS and associated findings: 8

T-cell (cellular) deficiencies

1) Predominant T-cell deficiency

DiGeorge anomaly (hypocalcemia, heart disease, aortic arch

Abnormalities, peculiar facies).

Chronic mucocutaneous candidiasis (endocrinopathies,

Thrush, & nail dystrophy).

Combined Immunodeficiency with Igs or Nezelof syndrome

(Bronchiectasis, diarrhea, & Thrush).

[18]

[T-cell (cellular) deficiencies—cont.]

Nucleoside phosphorylase deficiency (AR)

Natural killer cell deficiency (severe herpes viral infection).

Idiopathic CD4 lymphocytopenia (often asymptomatic).

2) Combined T- & B-cell deficiencies

XL lymphoproliferative syndrome (severe Epstein-Barr).

Wiskott-Aldrich Syndrome (XL) {eczema,thrombocytopenia,

Melena, & draining ears}.

Short-limbed dwarfism (cartilage-hair Hypoplasia, severe

Varicella).

Reticular Dysgenesis (pancytopenia).

Ataxia-telangiectasia (AR)-{dermatitis, Neurologic decline,

Sinopulmonary infections, & telangiectasia}.

Bare lymphocyte Syndrome (absence of HLA).

Adenosine deaminase deficiency (AR)-{skeletal abnormality}

Severe combined immunodeficiency (AR or XL)- {diarrhea,

Pneumonia, thrush, & failure to thrive}.

3) B-cell (antibody) deficiencies

X-linked agammaglobulinemia (Pyogenic infection after

Age 6, paralytic disease after oral polio

Immunization).

[19]

[B-cell (antibody) deficiencies—cont.]

Transient hypogammaglobulinemia of infancy (prematurity).

Common variable immunodeficiency (autoimmunity,

Splenomegally, malabsorption, & sinopulmon-

ary infections).

Immunodeficiency with thymoma (aplastic anemia).

Ig deficiency with hyper-IgM (XL)-{neutropenia and lymph-

Adenopathy}.

IgA deficiency (autoimmunity, respiratory or food allergy,

Respiratory infection often asymptomatic).

IgG subclass deficiencies (IgA deficiency).

Antibody deficiency with normal or elevated Igs (not proven).

4) Phagocytic disorders

Defects of cell movement

Hyperimmunoglobulinemia E syndrome (staph. Infections,

Eczema, & dermatitis, & course facial features).

Leukocyte adhesion defect type 1 (AR)-{prolonged attach-

ment of umbilical cord, leukocytosis, periodontitis).

Defects of microbial activity

Chediak-Higashi Syndrome (AR)-{giant granules of neutro-

phils, oculocutaneous albinism, neutropenia, and

recurrent infections}.

[20]

[Phagocytic Disorders—cont.]

Myeloperoxidase deficiency (AR)- {not proven}

Neutrophil G6PD deficiency (not proven)

Chronic granulomatous disease (XL or AR)- {lymphadenop-

athy, dermatitis, antral obstruction, small bone

osteomyelitis, & pneumonias}.

Abbreviations:

XL= X-linked Ig= immunoglobulins AR= autosomal recessive

ACD= autosomal codominant AD= autosomal dominant

SECONDARY IMMUNODEFICIENCY DISORDERS 8

Heredity & Metabolic Diseases Infectious Diseases

1) Down Syndrome 1) Congenital Rubella

2) Uremia 2) Measles

3) Diabetes Mellitus 3) Varicella Zoster

4) Malnutrition 4) HIV infection

5) Sickle cell disease 5) Cytomegalovirus (CMV)

6) Myotonic dystrophy 6) Infectious Mononucleosis

7) Protein-losing enteropathies 7) Acute bacterial disease

8) Nephrotic syndrome 8) Severe mycobacterial/

9) Vitamin deficiencies fungal disease

10)Mineral deficiencies [21]

Infiltrative/ Hematologic Diseases Immunosuppressive agents

1) Sarcoidosis 1) Anti-T-cell monoclonal

2) Hodgkin’s disease/Lymphoma antibodies

3) Histocytosis 2) Anti-lymphocyte globulin

4) Myeloma 3) Anti- thymocyte globulin

5) Leukemia 4) Radiation

6) Agranulocytosis 5) Corticosteroids

7) Aplastic anemia 6) Immunosuppressive

drugs

Miscellaneous

1) Aging

2) Anticonvulscent drugs

3) Graft-vs-Host disease [GVHD] (maculopapular rash, lymphadenopathy,

hepatosplenomegally, & alopecia).

4) Alcoholic Cirrhosis

5) SLE

6) Chronic Active Hepatitis

[22]

PROGNOSIS OF PRIMARY IMMUNODEFICIENCIES 8

Poor

X-linked lymphoproliferative syndrome (highly sensitive EBV infections)

Ataxia-telangiectasia (Cerebellar ataxia, telangiectasia of conjunctiva &

Skin, recurrent sino-pulmonary infections, & variable immuno-

logic disease).

Wiskott-Aldrich syndrome (eczema, recurrent infection, & thrombocyto-

penia).

Leukocyte-adhesion deficiency (disorder of WBC, poor wound healing,

leukocytosis, periodontitis, progressive necrotic soft tissue

infection, & delayed umbilical cord detachment).

Severe combined Immunodeficiencies (hereditary deficiency T- & B-cell

Systems, lymphoid aplasia, & thymic dysplasia).

Guarded

Hyper-IgE syndrome (recurrent staphylococcal infections of the skin, &

highly elevated IgE levels).

DiGeorge anomaly (absence/Hypoplasia of the parathyroid & thymus

glands, partial or complete T-cell immunodeficiency, &

near normal or normal B-cell immunity).

Hyper-IgM syndrome (elevated levels of IgM, decreased levels of IgA & IgG,

Susceptibility to infection, & intermittent neutropenia).

[23]

[Miscellaneous—cont.]

Chronic granulomatous disease (disorder of WBCs bactericidal function,

hypergammaglobulinemia, anemia, leukocytosis, & wide-

spread granulomatous lesions of the skin, lungs, and lymph

nodes).

Common variable immunodeficiency (decreased Ig & antibody levels &

Recurrent bacterial infections).

Good

IgG subclass deficiency (an antibody deficiency associated with

susceptibility to infections).

Complement deficiencies

Chronic mucocutaneous candidiasis (persistant Candidia infections of the

nails, skin, scalp, & mucous membranes often associated

with endocrinopathies mostly hypoparathyroidism and

hypoadrenalism).

Selective IgA deficiency ( IgA with normal levels of Igs).

Transient hypogammaglobulinemia (self-limited antibody deficiency).

X-linked agammaglobulinemia (panhypogammaglobulinemia, low or

abscent B cells, intact cellular immunity, and the onset of

infections after age 6).

[24]

AUTOIMMUNE DISORDERS 8,10, 17 are disorders in which the immune

system produces autoantibodies to an endogenous antigen resulting in injury to

the tissues involved by forming antibodies against the body’s own cells.

Autoantigens normally present in the internal cells stimulate the development of

autoantibodies act against the internal cell to cause localized and systemic

reactions resulting in a variety of diseases. The diseases most often considered

in autoimmune disorders are:

1) Hashimoto’s Thyroiditis, 2) SLE, 3) Goodpasture’s syndrome, 4)

Pemphigus, 5) Graves’ Disease, 6) Myasthenia Gravis, 7) Rheumatoid

Arthritis (RA), 8) Polymyositis, 9) Idiopathic Addison’s Disease, 10)

Bullous Pemphigoid, 11) Sjogren’s Syndrome, 12) Vitiligo, 13) Vasculitis,

and 14) some endocrinopathies.

Hashimoto’s Thyroiditis: is associated with antibodies to thyroglobulin, a

second colloid antigen, the microsomes of thyroid epithelial cells, and a thyroid

cell surface antigen. This disease is 20x more prevalent in women than in men.

The goiter is asymptomatic, but there is difficulty in swallowing, a feeling of local

pressure, the thymus is usually enlarged, & regional lymph nodes are

hyperplastic. Other names for this disease are Hashimoto’s Disease,

Lymphocytic Thyroiditis, Struma Lymphomatosis, & Hashimoto’s Struma.

[25]

Systemic Lupus Erythematosis (SLE) is an example of collagen disease

affecting many systems of the body. The pathologic characteristics are severe

Vasculitis, renal involvement, & lesions of the skin & nervous system. Viral

infection or dysfunction of the immune system may be the cause of this disease.

It is 4x more common in women than in men. The erythematous rash (“butterfly

rash”) over the nose & malar eminences,

fatigue, weakness, loss of weight, photosensitivity, fever, alopecia, & skin lesions

spreading to the mucous membranes. Also, pleuritis, glomerulonephritis,

peritonitis, pericarditis, neuritis, & anemia may be involved. Immunofluorescence

shows the presence of IgM, IgA, IgG, C3, & fibrinogen in the basement

membrane zone.

Goodpasture’s Syndrome is a chronic relapsing pulmonary hemosiderosis

associated with glomerulonehritis characterized by a cough with hemoptysis,

anemia, dyspnea, & progressive renal failure. The severe cases may be treated

by hemodialysis and kidney transplantation. It is characterized by circulating anti-

glomerular basement membrane antibodies in the blood and linear deposition of

immunoglobulins & complement in the glomerular basement membrane causing

pulmonary hemorrhage with progressive glomerulonephritis. This syndrome can

be rapidly fatal with pulmonary hemorrhage and respiratory failure as the cause

of death.

[26]

Pemphigus is a severe disease of the skin & mucous membranes characterized

by intraepidermal bullae and extensive erosions on apparently healthy skin &

mucous membranes. In active Pemphigus the serum & skin readily demonstrate

IgG antibodies binding to the site of the epidermal damage. The primary lesions

are flaccid bullae that upon pealing off leave painful erosions. The lesions may

be localized to the face and may need to be differentiated from Seborrheic

Dermatitis or Subacute Cutaneous Lupus Erythematosis; as well as, Exfoliative

Dermatitis. In addition, there are other disease entities that should be ruled out.

They are Bullous Pemphigoid, Benign Mucosal Pemphigoid, drug eruptions,

Erythema Multiforme, Dermatitis Herpetiformis, & Bullous Contact Dermatitis. In

Pemphigus Vulgaris the epidermis is easily detached from the underlying skin

(Nikolsky’s sign) & biopsy yields suprabasal epidermal cell separation. This

separation does not occur in Pemphigus Foliaceus in the suprabasal region, but

it does occur in the upper layers of the stratum spinosum or stratum granulosum.

Another test (Tzanck cell) shows the presence of acantholytic cells, typical of

Pemphigus. Cicatricial Pemphigoid [CP] (Benign Mucous Membrane

Pemphigoid) is a chronic

vesiculobullous autoimmune disorder with the most common clinical feature

being Desquamative Gingivitis (Nikolsky’s sign).

[27]

Direct immunofluorescence (DIF) is of great diagnostic value, since in CP, DIF of

mucosal biopsies reveal IgG, C3, & other Ig & fibrin deposits. Sometimes IgA &

IgM may be present.

GRAVES’ DISEASE is a disorder characterized by hyperthyroidism, enlarged

thyroid gland, exopthalmus (protrusion of the eyes), familial, autoimmune, 5x

more common in women than in men, exacerbated by stress or emotional upset,

nervousness, hand tremors, weight loss, fatigue, breathlessness, palpitations,

tachycardia, frontal bossing, heat intolerance, metabolic rate, gastrointestinal

motility, enlarged thymus, hyperplasia of the lymph nodes, blurred or double

vision, localized edema, atrial arrythmias, & osteoporosis. This disease is also

called Exopthalmic Goiter, Toxic Goiter, Thyrotoxicosis, or Diffuse Toxic Goiter.

Graves’ disease is caused by an antibody directed against the TSH receptor on

the thyroid follicular cell (TRAb).

MYASTHENIA GRAVIS is characterized by chronic fatigue, muscle weakness

(face & throat) due to the inability of neural receptors at the myoneural junction to

depolarize due to a of acetylcholine bringing about the loss or dysfunction of

acetylcholine receptors.

[28]

The onset of symptoms are: 1) Ptosis of the upper eyelids, 2) diplopia,

weakness of the facial muscles, 3) muscle fatigability, 4) dysarthria, 5)

dysphagia, proximal limb weakness, 6) severe quadriperesis may develop, 7)

voice changes, 8) nasal regurgitation, & 9) choking. In Ocular Myasthenia Gravis

only the extraocular muscles are involved.

RHEUMATOID ARTHRITIS (RA) is a chronic, inflammatory, destructive,

deforming collagen disease. It is characterized by symmetric synovial

inflammation leading to thickening of the synovium and swelling of the joint.

Other names used for RA are; Atrophic Arthritis, Ankylosing Spondylitis, Juvenile

Arthritis, & Arthritis Deformens. Some Immunologic abnormalities (immune

complexes, plasma cells antibodies (rheumatoid factor [RF]), lymphocytes

primarily T-helper cells pro-inflammatory cytokines, TNFs, CSFs, all contribute

to increased number of lining cells that produce collagenase & stromelysin

contributing to cartilage destruction, & interleukins-1 lymphocyte production &

prostaglandins.

Hyperplastic synovial tissue (pannus) may erode cartilage & ligaments. The signs

& symptoms include: 1) joint tenderness, 2) synovial thickening, 3) hands, feet,

wrists, ankles primarily involved, 4) stiffness, 5) fatigue, 6) malaise, 7)

deformities, 8) flexion contractures, & 9) ruptured popliteal cysts that can mimic

deep vein thrombosis (DVT).

[29]

SLE may mimic RA, and polymyositis, polyarteritis, progressive systemic

sclerosis, and dermatomyositis all have to be differentiated from RA.

GOUT is a recurrent form of chronic arthritis of peripheral joints that may be

precipitated by minor trauma, overindulgence in purine-rich foods, too much

alcohol, fatigue, & emotional stress. Signs resemble an acute infection—swelling,

warmth, redness, tenderness, fever, tachycardia, chills, malaise, & leukocytosis.

POLYMYOSITIS is a connective tissue disease having degenerative and

inflammatory changes in the muscles; and, also in the skin (dermatomyositis).

Pain, insomnia, edema, deformity, sweating, and tension accompany

Polymyositis. Deposits of IgM, IgG, and picornavirus-like substances have been

found in muscle cells. The disease is most common between ages 5-15 & 40-60.

The disease is characterized by proximal muscle weakness, tenderness, pain,

rash, polyarthralgias, Raynaud’s phenomenon, dysphagia, pulmonary disease,

fever, fatigue, & weight loss. There is nonhistone ANAs.

IDIOPATHIC ADDISON’S DISEASE (IAD) is caused by complete or partial

failure of the adrenocortical function resulting from autoimmune process,

infection, neoplasm, or hemorrhage in the gland.

[30]

Characteristics of this disease are 1) bronze pigmentation of the skin & mucous

membrane, 2) weakness, 3) anorexia, 4) dehydration, 5) weight loss, 6)

decreased endurance, 7) GIT disturbances, 8) anxiety, 9) depression, & 10)

decreased tolerance to cold. There is an increased need for salt,

mineralocorticoids, & glucocorticoids from the increase in stress. IAD exhibits

humoral & cell-mediated cytotoxicity.

SJOGREN’S SYNDROME (SS) is an Immunologic disorder characterized by

deficient moisture production of the lacrimal (causing desiccation of the cornea &

conjunctiva), salivary (causing dental disorders), and other glands resulting in

dryness of the mouth, eyes, and other mucous membranes including vaginal

dryness. There are also loss of taste and smell. Sjogren’s syndrome is often

associated with Rheumatoid Arthritis, Waldenstrom’s Macroglobulinemia,

Lymphoma, and Raynaud’s phenomenon. Immunological tests that should be

done are antithyroid antibodies, immunoglobulins & gammaglobulins, rheumatoid

factors (RFs), cryoglobulins, and Sjogren’s antibodies [called SS-A & SS-B]. The

salivary & lacrimal glands are infiltrated with CD4+ T cells and some B cells. The

T- cells inflammatory cytokines (interleukins-2, interferon ). SS is an

autoimmune disease characterized by keratoconjunctivitis sicca (KCS) and

xerostomia. Retroviruses and Epstein-Barr virus have been implicated in the

etiology of SS.

[31]

Organ System Conditions in SS are:

1) SKIN (dry, sweat, Vasculitis, purpura)

2) SALIVARY & LACRIMAL GLANDS (enlarged, xerostomia, atrophy,

keratoconjunctivitis)

3) GASTROINTESTINAL TRACT ( dental caries, oral candidiasis,

hypochlorhydria, hepatomegaly, splenomegally, biliary cirrhosis)

4) RESPIRATORY (rhinitis, pharyngitis, obstructive pulmonary disease)

5) CARDIOVASCULAR SYSTEM (Raynaud’s disease, LE)

6) MUSCULOSKELETAL SYSTEM (RA)

7) HEMATOPOETIC SYSTEM (megaloblastic anemia, microcytic-

hypochromic anemia, leukopenia, hypergammaglobulinemia,

hypersedimentation).

VASCULITIS is an inflammatory condition of the blood vessels (allergic

vasculitis, segmented hyalinizing Vasculitis, necrotizing Vasculitis). The

predominant inflammatory cells are PMNs. Some diseases connected to

vasculitic disorders are: 1) Henoch-Schoelein Syndrome, 2) Pseudomonas

septicemia, 3) drug-induced vasculitis, 4) Erythema nodosum, 5) polyarteritis

nodosa, 6) Temporal arteritis, & 7) Takayasu’s arteritis. IgG & complements are

commonly found in vessel walls.

VITILIGO is a benign skin disease consisting of irregular patches of various sizes

completely lacking any pigment with hyperpigmented borders.

[32]

This disease may be familial and is associated with Addison’s disease,

pernicious anemia, Diabetes Mellitus, & Thyroid dysfunction, as well as an

elevation of serum antibodies to thyroglobulin, parietal cells, & adrenal

Cells allow us to think that this disease is both neurochemical and Immunological

in basis. There seems to be melanocyte antibodies. In Diabetes Mellitus there

are cell-mediated & humoral islet cell antibodies.

There are many LABORATORY TESTS in IMMUNODEFICIENCY profiling:

(These are some of the tests): 8

Screening tests advanced tests special/research tests

B-cell Deficiency B-cell enumeration Advanced B- cell pheno-

IgG, IgA, IgM (CD19,CD20) typing

Isoagglutinin titers IgG subclass levels Biopsies

IgD, & IgE levels Ig survival & secretory

levels

Ig synthesis

Phagocytic cell deficiency

IgE level WBC turnover Adhesion molecule assay

NBT dye test Phagocytosis assay (CD11b, CD18)

WBC count and Bactericidal assay mutation analysis

morphology Chemiluminesence Enzyme assays (MPO,

[33] Oxidase)

G6PD, NADPH

T-cell deficiency

Lymphocyte count & HLA typing Advanced T-cell

Morphology Chromosome analysis phenotyping

Proliferative response Cytokine/receptor

To mitogens, antigens, assays (IL-2,

& allogeneic cells IFN-, TNF-)

T-cell subset enumeration Cytotoxic assays

(CD3, CD4, CD8) (NK, CTL, ADCC)

Enzyme assays

(ADA, PNP)

Complement deficiency

CH50 activity Component assay Alternative pathway

C3, & C4 levels Opsonic assay activity

Activation assay (C3a, Functional assays:

C4a, C4d, C5a) chemotactic

factor, immune

Adherence

[34]

MUCOCUTANEOUS DISORDERS & PERIODONTAL PATIENTS: some brief

Autoimmune relationships: 8,10,17

Cicatricial Pemphigoid (CP) with DIF of mucosal biopsies there are IgG, C3, fibrin

deposits, & other IgG deposits in the basement membrane zone (BMZ). It is

possible that a BMZ antigen initiates a reaction of unknown stimulus triggering an

immunogenic signal in the antigen activating the B-cell immune system and the

synthesis of IgG antibodies initiating the complement activation.

Pemphigus Foliaceus (PF) by using indirect immunofluorescence (IIF) circulating

IgG autoantibodies primarily; however, IgA & IgM may also be present. Also, C3

must be present in the epithelial intercellular spaces.

Systemic Lupus Erythematosis (SLE) with DIF of the BMZ there are deposits of

IgM, IgA, IgG, C3, & fibrinogen. There is a predominance of T-cells; and, an

immunocytochemical analysis of the oral mucosa & the skin yield HLA-DR

antigen expression on keratinocytes.

Acquired Immunodeficiency Syndrome (AIDS) or (HIV): the best predictors of the

onset of AIDS are the total number of circulating CD4+ lymphocytes or CD4 count

and the level of HIV RNA in plasma (viral load). The disruption of T-lymphocytes

results in B-cell disregulation. Suppressor/ Cytotoxic CD8+ lymphocytes in HIV

infection. IgG & IgA antibody levels are increased in this disease. In 1980 AIDS

was referred to as Gay Related Immune Deficiency (GRID).

[35]

AIDS is often accompanied by a progressive decline in CD4 immune cells, which

is a marker for immune suppression. A healthy person may have a high T4 count

& a low T8 cell count; but, with AIDS the T4 count is low & the T8 count is high.

Patients with AIDS are usually deficient in iron, zinc, folic acid (B9), selenium,

pyridoxine (B6), cyanocobalamin (B12), beta- carotene (vit. A), tocopherol (vit. E),

thiamine (B1), riboflavin (B2), Pantothenic acid (B5), and ascorbic acid (vit. C).

Therefore, supplementation with these minerals and vitamins can be beneficial to

AIDS patients. Of course, this would be in conjunction with routine AIDS

treatment.

MEDIATORS of BONE RESORPTION: 18

BONE STIMULATORS BONE INHIBITORS

Interleukin-1 (IL-1) Interferon gamma (IFN)

Interleukin- 6 (IL-6) Osteoprotegerin (OPG)

Tumor Necrosing Factor (TNF) Estrogens

Parathyroid Hormone (PTH) Androgens

PTH-related Protein (PTHrP) Calcitonin (CT)

Prostaglandin E2 (PGE2) Cyclosporin

Macrophage-colony stimulating

Factor (M-CSF)

Receptor activator of NFkB (RANK)

RANK Ligand (RANKL)

1,25 dihydroxyvitamin D3 (vitamin D)

[36]

The gingival crevicular fluid (GCF) contains biochemical mediators (IL-1 ,

IL-1 , IL- 6, & TNF- ) that can show the metabolic status of the tissues of

the periodontium. These cytokines reflect the following:

1) Periodontal inflammation IL-1.

2) IL-1 levels after periodontal therapy.

3) IL-1 is synergistic with TNF- (lymphotoxin) in stimulating bone

resorption.

4) IL-1 alveolar bone loss.

5) levels of IL-1 & IL- 6 are associated with Eikenella Corrodens &

Prevotella Intermedia and continuous loss of attachment and bone.

6) IL- 6 levels are associated with continually progressing periodontitis.

7) levels of estrogen are associated with levels of bone resorbing

cytokines.

8) levels of PGE2 attachment & bone loss.

9) alkaline phosphatase (ALP) in GCF is higher than in serum.

10) collagenases (Elastase, Stromelysin, Collagenase) associated with

bone loss, inflammation, & probing depth.

11) Collagenase- 2 & Collagenase- 3 reflect peri-implant osteolysis.

12) Osteonectin (ON or SPARC) is elevated in sites with severe periodontitis

& in GCF.

[37]

13) Osteopontin (OPN) is related to probing depth & attachment loss.

14) Osteocalcin (OCN) not established in human GCF; but only in animal

experimental periodontitis.

15) Estrogen deficiency leads to accelerated bone loss.

16) Estrogen replacement therapy (ERT) gingival bleeding, & decreases

attachment loss.

17) Osteoprotegerin (OPG) can inhibit osteoclastic differentiation and

function.

18) When cells show two factors (bone morphogenetic protein- 4 [BMP-4], &

vascular endothelial growth factor [VEGF]) this causes an increase in

bone density.

19) Localized Aggressive Periodontitis (LAgP) is connected to some

functional abnormalities of neutrophils and there is severe periodontal

breakdown. These functional abnormalities are:

a) phagocytosis

b) killing of Actinobacillus Actinomycetemcomitans

c) Impaired leukotriene B4 (LTB4 ) synthesis

d) superoxide production

e) Chemotaxis

f) receptor expression

20) TNF- suppresses insulin action by its specific receptor activating

insulin resistance. [38]

21) TNF- produced by adipose tissue of obese patients is a risk factor for

periodontal inflammation, & TNF- stimulates osteoclasts to activate

bone resorption.

22) TNF stimulates lipolysis in adipocytes to release free fatty acids that may

induce insulin resistance.

23) TNF induces intracellular hydrogen peroxide, which inhibits tyrosine

phosphorylation of Insulin Receptor Substrate-1 (IRS-1).

24) TNF- vascular endothelial growth factor (VEGF) in human

Periodontal ligament (HPDL) cells angiogenesis in

Periodontitis.

25) ROXITHROMYCIN (RXM) inhibits TNF- mediated VEGF induction;

Perhaps another way to help treat periodontitis.

26) IL- 1(specific cytokine), IL- 10(a regulatory cytokine), IL- 8, &

RANTES (chemokines) is related to the development of chronic adult

periodontitis.

[39]

27) 19 Adhesins

(Fimbriae, membrane vesicles

Attachment to epithelial cells,

Teeth and other bacteria)

Bacteriocin Collagenase

(Kills streptococci, actinomycetes, (degrades connective tissue)

Other Aa strains)

Chemotaxis

Inhibitor A. actinomycetemcomitans Cytotoxin

(Acts on neutrophils) (Inhibits fibroblast

Proliferation)

Leukotoxin Endotoxin

(Kills leukocytes) (Causes bone resorbtion)

Immunosuppressive

factors Fe Binding Proteins

(Inhibits IgG & IgM production) (Inhibit Complement Activation)

Invasins

(Penetrates nonprofessional phagocytes)

Clarification of bacterial virulence that contributes to periodontal pathogenesis

will enhance our ability to prevent and manage periodontal diseases and perhaps

allow us to develop a vaccine against these diseases. Periodontal disease is

dependent upon bacteria and their interaction with the host tissues in mediating

their destruction. When the balance between Proteinases, mediators, and their

A. actinomycetemcomitans

[40]

28) FUNCTIONAL CLASSIFICATION of REPRESENTATIVE

CYTOKINES: 20

Family Members

Chemotactic IL-8, MIP-1, MCP-1, RANTES

Proinflammatory IL-1, IL-1, TNF- , IL-6

Anti- inflammatory IL-1Ra, IL- 4, IL- 10

Growth Factor PDGF, EGF, FGF, IGF, VEGF

Immunoregulatory IFN- , IL-2, 4, 5, 7

29) Epidermal Growth Factor (EGF)

30) Fibroblast Growth Factor (FGF)

31) Vascular Endothelial Growth Factor (VEGF)

32) Insulin-like Growth Factor (IGF)

33) Platelet Derived Growth Factor (PDGF)

34) Tumor Necrosis Factor (TNF)

35) Macrophage Inflammatory Protein (MIP)

36) Monocyte Chemotactic Protein (MCP)

37) Interleukin (IL)

38) Interleukin- 1 Receptor Antagonist (IL-1Ra)

39) Interferon (IFN)

40) Granulocyte- colony Stimulating Factor (G-CSF)

[41]

41) Granulocyte Macrophage- Colony Stimulating Factor (GM-CSF)

42) IGF-1 is Chemotactic for periodontal ligament fibroblasts, osteo-

blasts, and osteoclast- progenitor cells. 21

IGF-1 is mitogenic for osteoblasts and periodontal ligament fibro-

Blasts and stimulates extracellular matrix synthesis.21

43) There are several diseases characterized by neutrophil- mediated

tissue injury: 22

a) Reperfusion injury h) CR3 deficiency

b) Acute respiratory distress syndrome i) Specific granule

c) Diabetes Mellitus deficiency

d) Inflammatory Bowel Disease (IBD) j) Vasculitis

e) Rheumatoid Arthritis (RA) k) Periodontal

f) Asthma diseases

g) Emphysema l) Inflammatory

Bowel

Syndrome (IBS)

[42]

44) AUTOIMMUNE HEMOLYTIC ANEMIAS (AIHA) 8,10

a) Warm type (warm agglutinin disease)[>370C]

1) Idiopathic [IgG or IgG+C]

2) SLE, Lymphoma, Chronic Lymphocytic leukemia [rarely IgA or

IgM].

b) Cold type (cold agglutinin disease)[<370C]

1) Idiopathic [IgM]

2) Secondary (mycoplasma pneumoniae, infectious mononucleosis)

[C3b or C3d]

3) Paroxysmal cold hemoglobulinuria (PCH)[anti-P] occurs in some

patients with congenital or acquired syphilis.

TRANSPLANTATION is the transfer of living cells, tissues, or organs from a

donor to a recipient, with the intention of maintaining the functional integrity of the

transplanted material to the recipient. An allograft (homograft) is a graft between

genetically dissimilar members of the same species. Allografts are rejected

through either a cell-mediated or humoral immune reaction of the recipient

against transplantation antigens present on the membranes of the donor’s cells.

The Lymphocyte (cell) – mediated immune reaction against transplantation

antigens (Host vs. Graft reaction or HGVR) is the main mechanism of acute

rejection.

[43]

The role of humoral antibody in graft rejection is evident when the recipient has

been presensitized to human leukocyte antigen (HLA) in the graft. HLAs are

found in varying concentrations on almost all nucleated cells. The Immunologic

response to these antigens is the major cause of graft rejection episodes. HLAs

are divided into two classes based on structure & function (discussed

separately).

PROPERTIES of IMMUNOGLOBULIN CLASSES: 7-10, 17

Immunoglobulin Class Principal Functions

IgG Agglutination, detoxification,

Enhancement of phagocytosis,

Virus neutralization, recall

Response, opsonization.

IgM Agglutination, enhancement of

Phagocytosis, Cytolysis,

Complement fixation.

IgA Protection of mucosal surfaces,

Secretory immunity, key

Defender against viral infection

IgE Mediation of immediate type of

Hypersensitivity, allergy,

Parasite immunity.

[44]

IgD Control of lymphocytic activa-

Tion and suppression.

INFECTIONS in PATIENTS with IMPAIRED CELL- MEDIATED IMMUNITY: 8-

10, 17

Bacteria: Viruses:

Listeria Monocytogenes Herpes Simplex

Nocardia Varicella- zoster

Mycobacterium Tuberculosis Cytomegalovirus

Nontuberculosis Mycobacteria

Legionella Pneumophila

Fungi: Protozoa:

Histoplasma Cryptosporidium species

Coccidioides Toxoplasma gondii

Cryptococcus Pneumocystis carinii

Candida

Aspergillus

Zygomycetes

IMMUNOSUPPRESSIVE DRUGS:

Prednisolone (IV) [a Corticosteroid] {a glucocorticoids}.

Azathiopine (an antimetabolite) [orally or IV].

Cyclophosphamide (an alkylating agent) is used when the patient is not tolerating

Azathriopine.

[45]

Cyclosporine [CsA] (a fungal metabolite) [spares the bone marrow & acts to

inhibit T- cell proliferation & activation].

Tacrolimus (used for liver transplant patients). When substituted for CsA in cases

of gingival overgrowth (GE) there is a reduction in GE.

Antilymphocyte globulin (ALG) [used as an adjunct in chemotherapy].

Antithymocyte globulin (ATG) [used as an adjunct in chemotherapy].

Monoclonal antibodies {MOAB} (the murine monoclonal antibody – OKT3- can

reverse rejection by binding to T- cell antigen- receptor complex [TCR/CD3].

Irradiation is of limited use in transplantation.

C- REACTIVE PROTEIN, IL- 6, & Neutrophils if elevated in humans are

considered to be indicators as risk factors for cardiovascular diseases.

PORPHYROMONAS GINGIVALIS if elevated in humans is also

considered to be an indicator for cardiovascular diseases (CVDs). P.Gingivalis is

also known to activate human gingival epithelial cells, spleen cells, and

peripheral blood monocytes the release of IL-1, IL- 6, IL- 8, & TNF- .

TNF- produced by the adipose tissue of obese patients is a risk factor

for periodontal inflammation; and, TNF- produced due to periodontal

inflammation may influence insulin sensitivity in both obese and type 2 diabetic

patients.

[46]

HUMAN GINGIVAL FIBROBLASTS (HGF) can be targets for TNF- & IL-

1 I in periodontal diseases. An important effect of IL-1 and TNF- is to

stimulate fibroblasts production of metalloproteinase (MMP) & stromelysin

(MMP- 3), which degrade components of the extracellular matrix in rheumatoid

arthritis & periodontitis. Both TNF- & IL- 1 induce bone resorption. Excess IL-

6 is produced in chronic periodontitis. Anti-

cytokine therapy can reduce inflammation, but the immune system is also

downregulated the risk of bacterial infections. Is the cure worth the

hardships? Only when we can control both (inflammation & the chance for

bacterial infection)!

GINGIPAINS 23 are trypsin- like cysteineproteinases produced by Porphyromonas

Gingivalis (P. Gingivalis) that is a major contributor to periodontitis. Gingipains

degrade macrophage CD14 and inhibit activation of leukocytes through

lipopolysaccharide (LPS) receptors sustaining the colonization of P. Gingivalis. 24

There are three Gingipains (HRgpA, RgpB, & Kgp) that have received the bulk of

the current research. A vaccination may be beneficial in treating periodontitis.

[47]

The following is a partial list of the proteases produced by P. Gingivalis: 9,23,24,31,34

Enzyme Gene Class Function(s) Effect

Arg-gingipain rgpA Cysteine improves proteolytic Increased PMNs to

(RgpA) Efficiency site of infection.

Arg-gingipain rgpB Cysteine same as rgpA but enhances vascular

(RgpB) lacks the adhesin permeability but not

Domain as effective as RgpB.

Lys-gingipain Kgp Cysteine encodes an adhesin Decreases

(Kgp) Domain Phagocytosis.

Prolyltripeptidase ptpA Serine Aids in generating same as function.

(PtpA) Tripeptides used in

Bacterial nutrition

Prolyldipeptydyl dpp Serine Cleaves dipeptides May aid in gener-

Peptidase IV from the amino-term- ating dipeptides

inal end used in bacterial

Nutrition.

Collagenase prtC Metallo- Degrades Type I Does not degrade

Protease Collagen gelatin.

[48]

Other Conditions Associated with Immunologic Defects:

1) Linear IgA Disease with DIF shows linear deposits of IgA at the epithelial-

connective tissue junction.

2) Discoid Lupus Erythematosis (DLE) with DIF shows positive, granular-

linear basement membrane (BM) deposits of Ig.

3) Systemic Lupus Erythematosis (SLE) with DIF shows the same as DLE.

4) Lichen Planus shows no immunoglobulins, complements (coarse granular

deposits, & usually fibrinogen.

5) Benign Lymphoepithelial Lesion (Mikulicz’s Disease) has excess T-helper

cells that stimulate B- cell antibody activity.

6) Macroglobulinemia shows IgM deposits. A malignant plasma cell

dyscrasia of B cells that normally synthesize & secrete IgM.

Treatment is with plasmaphoresis, alkylating agents (chlorambucil),

Melphalan or Cyclophosphamide, Prednisone, Fludarabine, &/or 2-

chlorodeoxyadenosine may be used.

7) Multiple Myeloma shows IgG, IgA, light-chains (Bence – Jones protein)

only, IgD & IgE are non-secretory. Treatment is with alkylating agents,

prednisone, & local radiation.

8) Nonhereditary Primary Systemic Amyloidosis shows light-chains (Bence –

Jones protein) only, but on occasion intact immunoglobulin molecules

(IgG, IgA, IgD, IgM).

[49]

9) Heavy Chain Malignant Plasma Cell Dyscrasias may show:

a) IgG heavy- chain () disease (elderly patients). Treatment

With alkylating drugs (vincristine), corticosteroids, and x-rays.

b) IgA heavy- chain () disease (Middle East children). Treatment

is with broad- spectrum antibiotics, Corticosteroids, and Cytotoxic

drugs.

c) IgM heavy- chain () disease (chronic lymphocytic leukemia).

Treatment is symptomatic. Almost as rare as IgD form.

d) IgD heavy- chain () disease (rare). Treatment is symptomatic.

Currently only 2 cases have been confirmed through 1998.

10) Minor Apthous Ulcers shows a defect in their cell- mediated

response. T4 helper/inducer lymphocytes are seen in early stages.

Basal cells express HLA-DR antigens. These are associated with

Crohn’s Disease.

11) Major Aphthous Ulcers (Periadenitis Mucosa Necrotica Recurrens or

PMNR) shows the same Immunologic responses as in cases of Minor

Aphthous Ulcers except that the lesions may appear for 6 weeks rather

than 7- 10 days.

12) Herpetiform Aphthous Ulcers shows T4 lymphocytes and

eventually more T8 lymphocytes than T4 lymphocytes. Macrophages

and Mast cells are common at the ulcer base. Healing occurs in 1- 2

weeks.

[50]

13) Becket’s Syndrome is an immune dysfunction accompanied by

vasculitis. Human Leukocyte Antigen (HLA- B51) is frequently present.

SALIVARY GLAND DISEASES:

1) Mikulicz’s Disease or Benign Lymphoepithelial Lesion may be unilateral

or bilateral in appearance with both dry mouth and dry eyes. T- helper

cells are in excess & stimulate B- cell antibody activity.

2) Sialadenitis is benign, painful, & swelling occurs involving one or more of

the salivary glands.

3) Sjogren’s Syndrome primarily affects women age 40 & is an

Immunologic disorder abnormal dryness of the mouth, eyes, & other

mucous membranes.

4) Immunologically CD4 & T- cells are abundant along with some

B-cells. (See Pg 17 for additional information).

5) Xerostomia (or Dry Mouth) is caused by cessation of normal salivary

secretion. This is a symptom of many diseases (diabetes, hysteria, acute

infections, Sjogren’s Syndrome, paralysis of the facial nerves, & adverse drug

reactions to antihistamines, antidepressants, antihypertensives, neuroleptics, and

parasympatholytics). Medications beneficial to relieving dry mouth are

Pilocarpine, Cevimeline, & Crystalline Maltose. Chewing gum has a tendency to

improve salivary flow.

6) Sialolithiasis is accompanied by swelling that increases at mealtime

or when eating a pickle. Located primarily in the floor of the mouth. Stone

formation either single or multiple are formed in these glands. [51]

SALIVARY IgA (Secretory immunoglobulin A or SIgA) is an antibody produced by

the body and found in all bodily secretions in the mucous membranes, lining the

intestines, in the bronchi, in saliva, and in tears. By combining with a protein in

the mucosa it defends body surfaces against invading microorganisms. The

synthesis of SIgA depends on locally activated CD4+ T cells. A deficiency in CD4+

T cells causes abnormalities in mucosal immune function including secretory

immunity. SIgA phagocytosis, and level of experimental clinical gingivitis.

SIgA inhibits the adherence of microorganisms to epithelial cells decreasing

mucosal infections. Patients with high levels of salivary IgA reactive with bacteria

in dental plaque may show a slower development of clinical experimental

gingivitis .25 Salivary IgA inhibits the adherence of microorganisms on epithelial

cells preventing mucosal infections 26. CD8 lymphocytosis syndrome (DILS) is a

subset of HIV disease; while, in Sjogren’s syndrome there is a predominance of

CD4 cells 27. In Necrotizing Ulcerative Periodontitis (NUP) there is an increase in

specific IgA output 28.

ENZYMES PRODUCED by PERIODONTAL MICROORGANISMS: 9

These enzymes appear to degrade almost all host tissues and intercellular matrix

molecules 29-34. (Modified April 2003 by Weinmann, SB).

Bacterial Enzyme Species Tissues Degraded

1) Collagenase P. Gingivalis Monocytes, PMNs function,

A. Actinomycetemcomitans neutrophil collagenase

MMP-8, bone resorption,

Depolymerizes collagen

Fibers. [52]

2) Trypsin-like P. Gingivalis Collagen, fibronectin,

A. Actinomycetemcomitans Immunoglobulins, MMP-

T. Denticola mediated tissue destruction

3) Keratinase P. Gingivalis

T. Denticola

4) Arylsulfatase (AS) C. Rectus inflammation

Bone loss clinically

Loss of attachment

5) Neuramidase P. Gingivalis An enzyme that catalyzes the

B. Forsythus cleavage of N-Acetyl neuraminic

P. Melaninogenica acid from muccopolysaccharides.

A hereditary deficiency of the

Enzyme causes sialidosis.

6) Fibronectin P. Gingivalis Fibronectin degradation.

Degrading P. Intermedia

Enzyme.

7) Phospholipase A P. Intermedia catalyze the hydrolysis of

P. Melaninogenica Phospholipase. They digest cell

Membranes, aid in the synthesis

Of prostaglandins, and helps in

The production of arachidonic

Acid.

[53]

Clarification of bacterial virulence that contributes to periodontal pathogenesis

will enhance our ability to prevent and manage periodontal diseases and perhaps

allow us to develop a vaccine against these diseases. Periodontal disease is

dependent upon bacteria and their interaction with the host tissues in mediating

their destruction. When the balance between Proteinases, mediators, and their

inhibitors (produced by host tissue cells) occurs net loss of tissue (active

periodontal disease) is the predominant result.

[56]

METABOLIC INTERACTIONS from BACTERIAL SPECIES found in DENTAL

PLAQUE may be schematically illustrated showing the intricate

interrelationship as follows: 9, 36-39

Streptococcus p-amino benzoate Streptococcus mutans

Actinomyces

CO2 Capnocytophaga

Lactate NH4+

Veillonella H2

Formate

Menadione Fusobacterium

Campylobacter

Protoheme Treponema

Succinate

Isobutyrate

Porphyromonas Gingivalis

Prevotella intermedia

Hemin -Globulin

Host [57]

The pathogenic organisms enter the body through one of three routes:

1) Direct penetration

2) Inhalation exogenous sources

3) Ingestion

Pathogens and commensal organisms may be involved with the establishment of

disease. Their virulence may be categorized as:

1) Highly virulent

2) Moderately virulent

3) Avirulent (Asymptomatic infection)

In order to establish disease an organism must be able to enter the host

And initiate infection; create phagocytosis of organisms by nonphagocytic

Cells, utilize host resources, prevent phagocytic uptake, reduce complement

activation, resist serums, destroy phagocytes and tissues, and interfere with the

immune system allowing the organism to multiply and survive within the host.

Some Diseases Linked to Various Organisms

Disease Infectious Agent Transmission & Concern

Liver Cancer, Hepatitis B & C Hepatitis B (blood & sexual contact).

Severe Liver Viruses Hepatitis C (blood & needles).

Damage Linked to Hepatocellular Carcinoma

And Cirrhosis of the liver.

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Some Diseases Linked to Various Organisms—cont.

Disease Infectious Agent Transmission & Concern

Ulcers, Stomach Helicobacter Pyloris 90% of peptic ulcer cases are

Cancer related to H. Pylori and Gastric

Cancer, but complete under-

Standing of H. Pylori’s spreading.

Heart Disease, Periodontitis Periodontal pathogens inhabit the

Premature Babies, mouth & transmitted via the saliva.

Stroke Risk factor for heart disease and

Premature birth.

Anal Cancer Sexually Transmitted Direct sexual contact during anal,

Diseases vaginal, and oral sex—primary

HPV.

Cervical Cancer Human Papilloma Direct sexual contact with an

Virus infected carrier.

Adult T-cell Human T-cell HTLV-1 can be transmitted thru

Leukemia Lymphotrophic blood, sexual contact, and mother

Virus to child. Common in Japan and

The Carribean.

Heart attacks, Chlamydia, Chlamydia spreads like a cold.

Clogged arteries Pneumoniae, There is a possible link to heart

Cytomegalovirus attacks & Atherosclerosis.

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Some Diseases Linked to Various Organisms—cont.

Disease Infectious Agents Transmission & Concern

Reactive Arthritis Salmonella, Shigella, The immune system lets the

Campylobacter allows the bacteria to attack the

Joints.

Depression & Borna Disease BVD may be transmitted from

Schizophrenia Virus (BVD) animals to humans & then thru

Direct contact from saliva.

Cancer and Epstein-Barr Virus Transmitted thru the saliva.

Upper & Posterior Nasopharyngeal Carcinoma.

Nasal Pharyngea

The ability of these organisms to produce disease is determined by the

organism’s virulent properties and the host’s ability to fight the disease process.

[60]

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