Periodontal Diseases- Host Response

Lecture given 10/28/2025

gingivitis

an inflammatory disease, can have acute or chronic inflammatory response (only determined by cell biopsy), is associated with dental biofilm, 3 histopathic stages

inflammation of gingival epithelium and connective tissue

periodontitis

an infectious-inflammatory disease, chronic disease, complex-multifactorial disease, initiated primarily by specific bacteria (predominantly gram negative anaerobes), cascade of host immune’s mechanism is activated, destruction of supporting tissues of the teeth

non specific plaque hypothesis

1890, miller

all bacteria are involved in disease

specific plaque hypothesis

1976, loesche

specific bacteria are involved in disease

updated non-specific plaque hypothesis

1986, theilade

all bacteria are involved in disease, difference is virulence factors

ecological plaque hypothesis

1994, marsch

specific pathogenic bacteria, ecological/environmental changes

keystone plaque hypothesis

2012, hajishengallis

specific pathogenic bacteria, ecological changes, host specific changes

health

host defense is effective against microbial challenge in a conductive environment for periodontal health

disease

reduced or defective host defense are ineffective against normal microbial challenge, increased microbial challenge overwhelms normal host defense

what immune cells/cytokines are present in the gingival sulcus in pristine gingiva?

neutrophils and IL-8

what changes are present in the gingival sulcus/junctional epithelium/connective tissue in initial lesion?

neutrophils, adhesion molcules like ICAM-1 and ELAM-1, few lymphocytes, macrophages

increased vascularity in connective tissue

what changes are present in the gingival sulcus/junctional epithelium/connective tissue in early lesion?

increased lymphocytes, neutrophils, plasma cells, fibroblasts (cell damage)

loss of gingival collagen

what changes are present in the gingival sulcus/junctional epithelium/connective tissue in established lesion?

increased GCF, mainly plasma cells, collagen and fibroblast damage, increased leukocytes in connective tissue

deepened gingival sulcus, more coronal connective tissue attachment level at the CEJ

what changes are present in the gingival sulcus/junctional epithelium/connective tissue in advanced lesion?

plasma cells, extensive damage to collagen fibers

deep periodontal pocket of 6mm or more, loss of connective tissue attachment, subgingival calculus covered by plaque, alveolar bone loss

what causes heat and redness in periodontitis?

vasodilation, increased blood flow

what causes swelling in periodontitis?

increased vascularity permeability, leakage of plasma proteins, accumulation of inflammatory cells

what causes pain in periodontitis?

stimulation of afferent nerves by chemical mediators of inflammation

specificity of the immune system

based on shape recognition of cell surface antigens

diversity of the immune system

any shape can be recognized by B or T lymphocytes which trigger an immune reaction

memory of the immune system

once a pathogen has actived the immune system, memory cells remain and will protect against a secondary infection

self-tolerance of the immune system

the immune system recognizes and differentiates between foreign invaders and self components

autoimmune disease

breakdown of self tolerance

immunodeficiency

defects in the immune system

innate immunity

non-specific, first line of defense, no memory

circulating molecules- complement

cells- phagocytes (neutrophils, macrophages), NKCs

soluble mediators- macrophage derived cytokines (inferferon, TNF)

inflammatory response

rapid response to microbes, limited diversity, no memory, PMNs/monocytes/NK cells, complement

adaptive immunity

specific/acquired, specialized immune response, memory, recognizes specific features of antigens

circulating molecules- antibodies, cytokines

cells- lymphocytes (t cells, b cells)

cellular immunity- t cell mediated

humoral immunity- b cell mediated

immunological response

microbial and non-microbial antigens, large diversity, has memory, lymphocytes (B and T), antibodies/cytokines

humoral-mediated immunity

antibody mediated, B lymphocytes, antibodies circulating in serum

primary defense against extracellular pathogens (bacteria and circulating viruses)

cell-mediated immunity

cell mediated, T lymphocytes, direct cell to cell contact of secreted soluble products (cytokines)

primary defense against intracellular pathogens (viruses, fungi, intracellular bacteria)

what are the key components of the host defense in periodontal diseases?

inflammatory responses, epithelium, saliva, humoral immune response, cell mediated response, mediators

inflammatory response in periodontal disease

rapid response of the tissues

functions to: dilute/wall off damaging microorganisms, kill microorganisms, and protect the host from bacterial invasion

GCF- forms as a result of acute inflammation, functions are washing non-adherent bacteria out of crevice, increasing in volume with increasing inflammation, contains mediators of inflammation and antibacterial agents

neutrophils- first line of defense

macrophages- important functions in both the inflammatory and immune responses

epithelium in periodontal disease

physical barrier to plaque microorganisms by epithelial cells being tightly attached to each other, keratinization, and the presence of a permeability barrier

inflammatory response- cell of the junctional epithelium release cytokines (IL-3, IL-1, TNFa) and cytokine induced chemoattractant 2, expression of host defense peptides like a and b defensins

immune response- langerhan’s cells (tissue macrophages) in the gingival epithelium

saliva in periodontal disease

antimicrobial effects supragingivally, no direct effects subgingivally

xerostomia predisposes to the development of supragingival plaque, gingivitis, and cervical caries

swallowing 0.5 L per day containing lots of bacteria

stimulates gut secretory immune system

salivary peroxidase system kills bacteria in saliva

lysozyme weakens gram positive bacteria

lactorferrin binds iron which is important for bacterial growth

humoral immune response in periodontal disease

antibody production

epithelial langerhan’s cells take antigenic material from microorganisms to lymph nodes and present it to circulating lymphocytes which recognize specific antigen and undergo clonal expansion

b lymphocytes differentiate into plasma cells that secrete antibody against specific antigen under the control of t helper lymphocytes

IgA and IgG- protective antibody production

antibody may be produces systemically or locally to aggregate microorganisms, stop them from adhering to epithelium, work with complement to lyse bacteria, and work with neutrophils for opsonisation and phagocytosis

cell mediated response in periodontal disease

t helper lymphocytes- produce cytokines, assist differentiation of b cells into plasma cells, activate neutrophils and macrophages

gingivitis- Th1 cells

periodontitis- TH2 cells, shift to B cells

mediators in periodontal disease

soluble chemical messengers that regulate/provide a link between inflammatory response, the immune response, and tissue damage

cytokines- can be pro or anti inflammatory, or transforming growth factor

prostaglandins

MMP

proteinases, proteinase inhibitors

cytokines

proteins, peptides, or glycoproteins that are secreted by specific cells of immune system

signaling molecules

mediate and regulate immunity, inflammation, hematopoiesis

pro-inflammatory cytokines

IL-1, IL-6, TNFa, IFNgamma, IL-8, IL-12, IL-18

anti-inflammatory cytokines

IL-4, IL-10, TGFb

what kind of cytokine is transforming growth factor beta (TGFb)

both pro and anti inflammatory

prostaglandins

PGE2- responsible for bone resorption, neutrophil chemotaxis, vascular permeability, and dilation

matrix metalloproteinases (MMP)

pro-inflammatory, degrade connective tissue

group of enzymes, responsible for the degradation of extracellular matrix collagen, increased expression in pathological conditions that can lead to tissue destruction

cytokine network

interleukins (IL), cytotoxic cytokines, colony stimulating factors (CSFs), interferons (IFNs), growth factors, chemokines

pleiotropic

a single cytokine can cause many different effects on the target cell

redundant

many cytokines can elicit the same response from their target

synergistic

effects of 2 cytokines on a target cell are more than additive

antagonistic

one cytokine is capable of blocking the effect of another cytokine

prostaglandins (PGE)

products of cox pathways

vasodilation or vasoconstriction, potent stimulus of bone resorption

leukotrienes (LTs)

products of LOX pathway, potent chemoattractants for neutrophils

what signaling molecules are most likely responsible for the prolonged phase of vascular permeability?

prostaglandins and leukotrienes

which MMP can be used as an indicator of disease severity?

MMP8

what are all the components of blood?

erythrocytes, thrombocytes (platelets), leukocytes, plasma

erythrocytes

RBCs, function in oxygen and carbon dioxide transport

thrombocytes

platelet, initiate the clotting cascade

end product of megakaryocytes, no nucleus for replication, live 5-9 days, play part in initial hemostasis with the platelet plug, also actively extrude growth factor involved with the initiation of wound healing

growth factors = cytokines (proteins stored in the alpha granules)

leukocytes

white blood cells, integral component of the immune response

plasma

fluid portion of the blood, contains soluble proteins important to homeostasis like antibodies, fibrinogen, kinins, complement, histamine, CRP, others

platelet rich plasma (PRP)

a source of growth factors that support soft tissue healing

blood clot

initiates soft tissue healing and bone regeneration

what is the composition of a natural clot?

95% RBCs, 4% PLT, 1% WBCs

what is the composition of a PRP clot?

95% PLT, 4% RBCs, 1% WBCs

this concentration enriches the natural clot to initiate a more rapid and complete healing process

what growth factors are found in PRP?

platelet derived growth factor-PDGF, found in alpha granules of platelets

transforming growth factor beta- TGFb, found in alpha granules of platelets

epidermal growth factor- EGF, stimulates angiogenesis and epithelial development

vascular endothelial growth factor- VEGF, stimulates angiogenesis, mitogenesis, and vascular permeability

fibronectin and vitronectin- cell adhesion molecules in plasma

fibrin- cell mobility in wound

c reactive protein (CPR)

a member of the class of acute phase reactants as its levels rise dramatically during inflammatory processes occuring in the body

thought to assist in complement binding to foreign and damaged cells and affect the humoral response to disease

eosinophil

granules have an affinity for eosin and stain pink

play a major role in the host response to parasitic invasion and bind IgE

granules contain lysozomal enzymes, major basic protein, eosinophil cationic protein, eosin derived neurotoxin, eosinophil peroxidase

basophil

granules are stained blue with hematoxylin

least abundant leukocyte

granules contain histamine, herparin, slow reacting substance of anaphylaxis, bradykinin

b cells

become programmed to produce antigen specific antibody

plasma cells

b cells that move into tissue, can aid in antigen presentation to t cells

t cells

different types have different roles in cell mediated immunity

NK cells

capable of killing tumor cells as well as virally infected and other cells

what kind of t cells are there?

memory, cytotoxic (CD8), NKT, helper (CD4)

immunoglobulins

heterogenous group of glycoproteins, consists of polypeptide chains linked by disulfide bonds, contain a minimum of 2 heavy chains and 2 light chains, variable domains are found on both heavy and light chains and each contains a hypervariable region, variable and hypervariable regions define the specificity to bacterial antigens

IgG

main immunoglobulin present in the blood, 70-75% of total Ig serum, initial defense in newborns

IgA

localized antibody protection on mucosal surfaces, secretory (saliva, tears, sweat, nasal fluids, ect)

IgM

major Ig present on the surface of immature B cells, binds with complement and causing agglutination and bacteriolysis, 1st Ig to take part in immune response

IgD

trace antibody in the serum, present on the surface of B cells

IgE

very low concentration in human serum, increases during allergic reactions and some parasitic infections, main Ig responding to infection caused by certain parasites

neutrophils (PMNs)

comprise 50-70% of circulating leukocytes, critical to the host defense against injury and infection, found in acute lesions in large numbers, decrease in numbers in more chronic lesions, phagocytosis is enhanced by complement receptors, play a central role in local tissue damage, first to localize into sites of infection

monocyte

play a direct role in cell mediated immunity, large, long living, highly phaogcytic, most abundant cell in later stages of inflammation, have receptors for the Fc portion of the IgG, process antigen which ultimately leads to the stimulation of T and B lymphocytes, are key producers of inflammatory mediators cytokines and prostaglandins in response to both host cells and bacterial components

marcophage actions in promoting inflammation

scavenger- responsible for phagocytosis of dead and dying cells

modulates fluid and cellular components of inflammation

secretes tissue degrading enzymes

secretes mediators like IL-1, TNFa, and prostaglandins

macrophage actions in promoting immunity

traps and presents antigens in the connective tissue while CD44 acts as an anchor

secretes IL-1 and TNFa

t cell dependent activation and phagocytosis

elimination of opsonized antigens

fibroblasts in health

collagen and MMP inhibitors leads to connective tissue regeneration and repair

fibroblasts in disease

MMPs leads to tissue destruction

what are the 2 major pathways of complement activation?

classical and alternative

classical pathway

follows the formation of an antibody-antigen complex

alternative pathway

involves direct activation of complement by endotoxins found in cell wall of gram negative bacteria (LPS)

c3a

activates basophils and mast cells causing release of vasoactive substances including histamines

c3b and c4b

opsonize the antigens together for easier phagocytosis by PMNs and macrophages

c5a

enhance PMN activation and chemotaxis

c5b, c6, c7, c8

form a membrane attack complex (MAC) that can destroy bacteria by punching a hole in their cell wall

what are the biologic effects of complement?

lysis, opsonization, activation of inflammatory response, clearance of immune complexes

what inflammatory effect do c3a and c5a have?

increase vessel permeability via mast cell degranulation and release of histamine

what inflammatory effect do c3b and c5a have?

production of oxygen radicals by leukocytes

what inflammatory effect does c5a have?

leukocytes migrate to blood vessel walls, neutrophil degranulation releasing enymes and oxygen radicals

what inflammatory effect does c3a have?

chemotactic for phagocytes

what inflammatory effect does c3b have?

chemokine production, macrophage activation, opsonization

what inflammatory effect do c5a and c567 complex have?

chemotactic for leukocytes

what inflammatory effect do c5b, c6, c7, c8, and c9 have?

cell lysis

what are the functions of the clotting cascade?

prevent the spread of infection and inflammation, clot formation to stop bleeding, clot formation to form a scaffold for repair and healing, chemotaxis of neutrophils, increased permeability of the vasculature

osteoimmunology

RANKL is master switch regulator

osteoblasts express RANKL on cell membrane

RANKL binds to RANKr which activates osteoclasts

OPG blocks RANKL from binding maintains bone homeostasis

concentrations of OPG/RANKL controlled by cytokines

what happens to the RANKL/OPG ratio during periodontitis?

it increases