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1

5.1 Secretory immunoglobulin-a

IgA1 vs. IgA2

IgA exists in two ______, IgA1 and IgA2.

While IgA1 predominates in _____ (~____%),

IgA2 percentages are higher in _______ than in ____ (_____ in secretions);

the ratio of IgA1 and IgA2 secreting cells___________________________of the human body:

IgA1 is the predominant IgA subclass found in serum. Most _____tissues have a predominance of____-_____ cells.

In IgA2, the heavy and light chains are not ____________, but with _____________. In secretory lymphoid tissues (e.g., _______________), the share of ________ production is larger than in the non-secretory lymphoid organs (e.g. _______________).

Both IgA1 and IgA2 have been found in _________ like ______, ____ and _____, where _____ is more prominent than in the _____. _____ antigens tend to induce more IgA2 than ____ antigens.

 

The dimeric IgA molecule.
1 _-chain
2 _-chain
3 _-chain
4 ______ ________

IgA1 vs. IgA2

IgA exists in two isotypes, IgA1 and IgA2. While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions); the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body:

IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA-producing cells.

In IgA2, the heavy and light chains are not linked with disulfide, but with monovalent bonds. In secretory lymphoid tissues (e.g., gut-associated lymphoid tissue, or GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs (e.g. spleen, peripheral lymph nodes).

Both IgA1 and IgA2 have been found in external secretions like colostrum, maternal milk, tears and saliva, where IgA2 is more prominent than in the blood. Polysaccharide antigens tend to induce more IgA2 than protein antigens.

2

Serum vs. Secretory IgA

It is also possible to distinguish forms of IgA based upon their ______- serum IgA vs. secretory IgA.

In secretory IgA, the form found in secretions, polymers of ___ IgA monomers are linked by ___________; as such slgA holds a molecular weight of ________.

One of these is the __ chain (joining chain), which is a _____ of molecular mass 15kD, rich with ______ and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells.

Serum vs. Secretory IgA

It is also possible to distinguish forms of IgA based upon their location - serum IgA vs. secretory IgA.

In secretory IgA, the form found in secretions, polymers of 2-4 IgA monomers are linked by two additional chains; as such slgA holds a molecular weight of 385,000.

One of these is the J chain (joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells.

3

Serum vs. secretory IgA

The oligomeric forms of IgA in the _____(mucosal) secretions also contain a _______ of a much larger molecular mass (70 kD) called the ________ ______ that is produced by _____ cells.

This molecule originates from the ____-__ receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but ____ ______) IgA across the _____ cells and into _____ such as tears, saliva, sweat and gut fluid.

Serum vs. secretory IgA

The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called the secretory component that is produced by epithelial cells.

This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid.

4

5.2 5.2 Lysozyme/Proteases

Present in numerous ___ and most ______

Oral LZ is derived from at least ____ sources

_____
_____
_____
_____

Biological function:

Classic concept of ________ activity of LZ is based on its ______ activity (______ ___ _______ bond between _____ and ____ in the _____ layer.

Gram ____ bacteria generally more ____ than gram ____because of outer ____  layer

Present in numerous organs and most body fluids

Oral LZ is derived from at least four sources

major and minor salivary glands, phagocytic cells and gingival crevicular fluid (GCF)

Biological function

Classic concept of anti-microbial activity of LZ is based on its muramidase activity (hydrolysis of b(1-4) bond between N-acetylmuramic acid and N-acetylglucosamine in the peptidoglycan layer.

Gram negative bacteria generally more resistant than gram positive because of outer LPS layer

5

Lactoferrin
_____ secretion from ____ and ___  glands

______ release into ____

Inactivated in presence of ________

Iron free state = _____-_________
Apo-lactoferrin does what? ________________

May lead to _____ if not _____ of the____ _____ from pathogenic microorganisms

Nutritional immunity (____ _______)

Some microorganisms (e.g., E. coli) have adapted to this mechanism by producing __________.

They_____________________than lactoferrin

Iron-rich enterochelins are then ______ by bacteria

Lactoferrin, with or without iron, can be _____________________.

In unbound state, a direct ___________

 

 


lSerous secretion from major and minor glands
lLeukocytes release into GCF
lInactivated in presence of high [Fe3+]
lIron free state = apo-lactoferrin
lApo-lactoferrin  irreversibly directly binds to bacteria
lMay lead to agglutination if not expropriation of the essential metal from pathogenic microorganisms

Nutritional immunity (iron starvation)

Some microorganisms (e.g., E. coli) have adapted to this mechanism by producing enterochelins.

bind iron more effectively than lactoferrin

iron-rich enterochelins are then reabsorbed by bacteria

Lactoferrin, with or without iron, can be degraded by some bacterial proteases.

In unbound state, a direct bactericidal effect

6

5.4  Histatins

Anti-_____activity

Histatin ____ is known to kill _____ _____

Increases_____ _____

Histatin ______ are known ____ _____ _____ that can migrate through epithelial tissues

Inhibit ____ ______

Histatin _

Anti-fungal activity

Histatin 5 is known to kill Candida albicans

Increases wound healing

Histatin 1 & 2 are known wound closing factors that can migrate through epithelial tissues

Inhibit matrix metalloproteinases

Histatin 5

7

5.6 Mucins/Agglutinins

Lack __________________

______  molecules with ___, _______ ______structure

____ backbone (____) with _____ side-chains

Side-chains may end in _____ charged groups, such as sialic acid and bound sulfate

____, _________ water (resists ________)

Unique ______ properties (e.g., high _____, _______, and low _____)

____ major mucins (____ and _____)

Lack precise folded structure of globular proteins

Asymmetrical molecules with open, randomly organized structure

Polypeptide backbone (apomucin) with CHO side-chains

Side-chains may end in negatively charged groups, such as sialic acid and bound sulfate

Hydrophillic, entraining water (resists dehydration)

Unique rheological properties (e.g., high elasticity, adhesiveness, and low solubility)

Two major mucins (MG1 and MG2)

8

5.6 Mucins/Agglutinins

___ _____

_____ coating about hard and soft tissues

Primary role in ______ of _______ ______

Concentrates ___________ molecules at ______ interface

 

______

Align themselves with _____________ (characteristic of asymmetric molecules)

Increases_____qualities (film strength)

Film strength determines how effectively ______________________.

 

_____ __ _______ ______

_____ adhere to ___ may result in_____, or

_________ may be unable to ___________

 

______ _______

Mucin oligosaccharides mimic those on __________________

React with _________, thereby blocking them

 

Tissue Coating

Protective coating about hard and soft tissues

Primary role in formation of acquired pellicle

Concentrates anti-microbial molecules at mucosal interface

Lubrication

Align themselves with direction of flow (characteristic of asymmetric molecules)

Increases lubricating qualities (film strength)

Film strength determines how effectively opposed moving surfaces are kept apart

Aggregation of bacterial cells

Bacterial adhere to mucins may result in surface attachment, or

 Mucin-coated bacteria may be unable to attach to surface

Bacterial adhesion

Mucin oligosaccharides mimic those on mucosal cell surface

React with bacterial adhesins, thereby blocking them

9

5.7 Cystatins

Are____  of ___________

Are ubiquitous in many ______ _____

Considered to be _____ against unwanted _____

  • _____ proteases
  • ____ ____

May inhibit proteases in _____ tissues.

Also have an effect on ____ ______ _______.

Are inhibitors of cysteine-proteases

Are ubiquitous in many body fluids

Considered to be protective against unwanted proteolysis

bacterial proteases

lysed leukocytes

May inhibit proteases in periodontal tissues.

Also have an effect on calcium phosphate precipitation

10

Summary
Anti-microbial proteins in Saliva


Statherin - a ___ that______________and allows for _______
Mucin - cause ____  to _____
Lysozyme -____ (depressed by ___ and ___)
Lactoferrin - combines with ____ and ____ to _____ _____ and ___________

Salivary peroxidase - reacts with salivary ______ when _____ is around and forms _____ which _______________________.
Lactoperoxidase - adsorbs to ______ altering ______________.
Histatins – ______ _____ _____
Cystatins –Affects _________________.

 


Statherin - a PRP that stabilizes inorganic ions and allows for supersaturation
Mucin - cause bacteria to aggregate
Lysozyme - antibacterial (depressed by iron and copper)
Lactoferrin - combines with iron and copper to protect lysozyme and deprives bacteria of these metals
Salivary peroxidase - reacts with salivary thiocyanate when H2O2 is around and forms hypothiocyanite which inhibits bacterial glucose metabolism
Lactoperoxidase - adsorbs to hydroxyapatite altering primary bacterial attachment
Histatins – Antimicrobial wound closers
Cystatins – Affects mineral balance of the tooth

 

11

Physiological Harmony

Altered Oral Ecology

Mechanical Prop, Stimulus, Acinar cells

Substrate, Bacteria, Host

12

Etiology of Salivary Hypofunction

• D_______________________ (e.g., ____ ______)-->_______
•M___________ (e.g., ________)--> _____
•M___________________ (e.g., ______)-->_____
•D______________ (e.g., _____)--> _____
•A________________--> ______

 


•Damage to Acinar Units (e.g., radiation, Sjogren’s)-->acinar
•Medications (e.g., blocking agents)--> stimulus
•Mechanical obstruction (e.g., sialoliths)-->mechan
•Dehydration (e.g., diuretics)--> acinar
•Chronic alcoholism--> acinar
•Sialolith
 

13

The Cascading Effect of Saliva Loss

Decrease salivary flow

  • Mild moderate and severe_______
    • ____ and ____
    • Difficulty___, ____ and____
    • ____ ____ ____, ___ ____

Decrease salivary flow

  • Mild moderate and severe dry mouth
    • Discomfort and Pain
    • Difficulty chewing, swallowing and speaking
    • Oral fungal infections, tooth decay

14

Xerostomia

  • Dry mouth
  • Clinical History
  • History of ____
    • Yes
      • _____
    • no
      • _______
      • ________
      • _________
        • Yes
          • _________
        • No
          • ____
          • _____
          • _____
          • ______
            • yes
              • ______
            • No 
              • ______

  • Dry mouth
  • Clinical History
  • History of Radiotherapy
    • Yes
      • Post-radiation Xerostomia
    • no
      • Sialometry
        • Reduced Saliva rate
        • History of xerogenic med intake
          • Yes
            • Pharmacological Xero
          • No
            • Dry eyes
              • + SS serum
              • + Lip biopsy
              • Conn tissue disease?
                • yes
                  • secondary SS
                • No 
                  • primary SS 

15

 ~ Causes of Non-neoplastic ~
~ Salivary Gland Enlargement ~

 

____
____
_____
_____

Infection

Inflammation

Obstructive

Co-Morbitity Effects

16

Infection

____ ______ - ___ (___, ____),____

____ ____ ______

_____ _____- _____ ,_____

Acute sialadenitis - viral (mumps, CMV), bacterial

Recurrent acute sialadenitis

Chronic sialadenitis - tuberculosis, actinomycosis

17

~ Acute Sialadenitis Mumps ~

_____ cause of acute ____ swelling of the ____ gland in _____

Due to _______ infection

____-  illness is followed by acute____ painful parotid swelling

Resolves ______ over ____ days

Occasionally parotid swelling may be____

Occasionally may affect ____________

Similar clinical picture may occur with ____________or _______ _____ ____

Commonest cause of acute painful swelling of the parotid gland in children

Due to paromyxovirus infection

Flu-like illness is followed by acute bilateral painful parotid swelling

Resolves spontaneously over 5 -10 days

Occasionally parotid swelling may be unilateral

Occasionally may affect submandibular glands

Similar clinical picture may occur with Coxsackie A or B or parainfluenza virus infection 

18

~ Bacterial Sialadenitis ~

Acute ascending bacterial sialadenitis usually affects the____ glands

Due to __________ or_________ infection

Incidence of this condition is ____

Used to be seen in _______________ patients with ____________

Presents with ____ tender swelling of the ____ gland

____  can often be _________

Sialogram is______

Treatment is with _____ ____-____ _____

Late presentation can cause a ______ _____ to develop 

Acute ascending bacterial sialadenitis usually affects the parotid glands

Due to staphylococcus aureus or streptococcus viridans infection

Incidence of this condition is decreasing

Used to be seen in dehydrated post-operative patients with poor oral hygiene

Presents with painful tender swelling of the parotid gland

Pus can often be expressed from the duct.

Sialogram is contraindicated

Treatment is with parenteral broad-spectrum antibiotics

Late presentation can cause a parotid abscess to develop 

19

~ Salivary Gland Enlargement ~

INFLAMMATION

___ ____

______

_____ ____

____ ____ _____ _____

______ _____

____

Sjogren's syndrome

Sarcoidosis

Mikulicz's syndrome

Diffuse infiltrative lymphocytosis syndrome

Granulomatous sialadenitis

Idiopathic

20

~ Diffuse Infiltrative Lymphocytosis Syndrome ~

Diffuse infiltrative lymphocytosis syndrome

___  lymphocytic infiltrate associated with ____

Often involves____ _____ (present in __-__% of US HIV+ patients vs. up to __% in Africa)

Also affects ___ glands, ___, ___, ___, ___,____, __, _____

____ on ___ scale, 0: _____, 4: __________ of 50 or more mononuclear cells in a 4-mm2 area of a section

Micro: resembles_____  syndrome; ____ ____ ____ atypia common in advanced HIV patients

Diffuse infiltrative lymphocytosis syndrome

CD8+ lymphocytic infiltrate associated with HIV

Often involves salivary glands (present in 1-6% of US HIV+ patients vs. up to 50% in Africa)

Also affects lacrimal glands, kidney, muscle, nerve, liver, lung, GI, breast

Graded on 0-4 scale, 0: no infiltrate, 4: 2+ foci of 50 or more mononuclear cells in a 4-mm2 area of a section

Micro: resembles Sjogren’s syndrome; salivary ductal epithelial atypia common in advanced HIV patients

21

Mikulicz’s Disease

Also called ____ ___________ _____

Presents as ____ _____, ____  enlargement of____ and ____ glands

May ____ during acute____

May be confined to ________, usually part of ___

Increased incidence with ____

Initially polyclonal, may evolve into _____ (diffuse large B cell, rarely Hodgkin’s lymphoma, peripheral T cell lymphoma)

Gross:__________areas and occasional ___

Also called benign lymphoepithelial lesion

Presents as slow, bilateral, symmetric enlargement of salivary and lacrimal glands

May subside during acute infections

May be confined to salivary gland, usually part of Sjogren’s syndrome

Increased incidence with HIV

Initially polyclonal, may evolve into lymphoma (diffuse large B cell, rarely Hodgkin’s lymphoma, peripheral T cell lymphoma)

Gross: solid gray-white areas and occasional cysts

22

Mikulicz's Disease

First reported in 1890 

Painless

Which glands? Parotid and Submandibular

Elevated serum IgG4 conc

infiltration of plasma cells expressing IgG4 with fibrosis

One of the igG4- related sclerosing diseases 

Mikulicz's Disease

First reported in ___

___

Which glands?

____ ____ ____ ____

infiltration of plasma cells expressing ___ with ___

One of the ___- ____ ______ diseases 

23

~ Mikulicz’s Disease ~

Description:

Benign and chronic dacryoadenitis with bilateral painless swelling of lacrimal and salivary glands and____  or ____ _______.

Associated with ____ and ____ but _____ and ______.

It may be caused by t____, l____,l_____,p______, s_____, s_____, or g_____.

Onset may occur in conjunction with ______________,____ infection, or ______.

Some authors consider this disease and the Sjögren syndrome as identical, but others suggest they are separate entities because of the absence of _________ in Mikulicz disease.
 

Description: Benign and chronic dacryoadenitis with bilateral painless swelling of lacrimal and salivary glands and decreased or absent lacrimation.

Associated with dry mouth and dry eyes but no arthritis, and vision blurring.

It may be caused by tuberculosis, leukemia, lymphosarcoma, poisoning, sarcoidosis, syphilis, or gout.

Onset may occur in conjunction with respiratory tract infection, oral infection, or tooth extraction.

Some authors consider this disease and the Sjögren syndrome as identical, but others suggest they are separate entities because of the absence of rheumatoid arthritis in Mikulicz disease.
 

24

~ Mikulicz’s Disease ~

Micro: marked _______ _____ with lymphoid follicles surrounding solid epithelial nests;

also scattered____  and _____cells;

excess ____ basement membrane material ______ between cells;

also ____ ____and _____,

_____ lesions,

_____ B cells

; usually no ____,

no involvement of ____ ducts

Micro: marked lymphocytic infiltration with lymphoid follicles surrounding solid epithelial nests; also scattered histiocytes and dendritic cells; excess hyaline basement membrane material deposited between cells; also acinar atrophy and destruction, lymphoepithelial lesions, monocytoid B cells; usually no fibrosis, no involvement of large ducts

25

~ Sarcoidosis ~

Sarcoidosis  is a ____ _____ disorder they may also affect the _____ ____.

Usually, however, it affects the ___, ____, ___, ___, ___and ___.

_________  is used for definitive diagnosis.

Clinically, the____ gland exhibits a ___ ______ enlargement with decreased salivary function.

There is _____ present upon milking of the parotid gland.

Therapy is ____, with _____ treatment.

Sarcoidosis  is a systemic granulomatus disorder they may also affect the parotid gland.

Usually, however, it affects the heart, lungs, muscles, eyes, liver and central nervous system.

Lymph node biopsy is used for definitive diagnosis.

Clinically, the parotid gland exhibits a bilateral asymptomatic enlargement with decreased salivary function.

There is no pus present upon milking of the parotid gland.

Therapy is symptomatic, with corticosteroid treatment.

26

~ Salivary Gland Enlargement ~

Obstructive

____

____- __________, ____

Obstructive

Calculi

Cysts - mucous retention, ranula

27

~ Sialolithiasis ~

Of all salivary stones:

___% occur in the submandibular gland
____% occur in the parotid gland
___% occur in the sublingual gland

___% of submandibular stones are _____

Most parotid stones are ____

The classic presentation of a submandibular stone is____________

This does however requires almost____  obstruction of the submandibular duct

If partial obstruction occurs swelling may be__________

If diagnostic doubt then stone can be demonstrated by _____

Treatment is by either 

The stone should be removed if 

The gland should be

The role of extracorporeal lithotripsy is currently under investigation 

Of all salivary stones:

§80% occur in the submandibular gland
§10% occur in the parotid gland
§7% occur in the sublingual gland

80% of submandibular stones are radio opaque

Most parotid stones are radiolucent

The classic presentation of a submandibular stone is pain and swelling prior to or during meal

This does however requires almost complete obstruction of the submandibular duct

If partial obstruction occurs swelling may be mild with chronic painful enlargement of the gland

If diagnostic doubt then stone can be demonstrated by sialogram

Treatment is by either removal of stone from duct or excision of the gland

The stone should be removed if palpable with no evidence of chronic infection

The gland should be excised if the stone posterior or gland is chronically inflamed

The role of extracorporeal lithotripsy is currently under investigation 

28

~ Ranula ~

Defined as a large retention cysts in the ducts of the___________.

The lesions are large, ______ with pronounced ____

Treatment is by ____ or _____

Defined as a large retention cysts in the ducts of the submandibular, sublingual, or mucous glands of the floor of the mouth.

The lesions are large, blue-purple-pink with pronounced vascularity.

Treatment is by excision or marsupialization.

29

~ Mucocele (Mucocyst) ~

Mucoceles or Mucocysts are ___ cysts othe ___salivary glands of the _________.

All though they are most frequently observed on the ___ ________, the can also be found on the ___ and the _____

The lesions are ___ , ___ swellings often ___ in appearance.

Treatment is by ___________

Mucoceles or Mucocysts are retention cysts othe minor salivary glands of the labial mucosa.

All though they are most frequently observed on the mandibular labial mucosa, the can also be found on the palate and the floor of the mouth.

The lesions are large , ovoid swellings often bluish in appearance.

Treatment is by excision or marsupialization.

30

~ Salivary Gland Enlargement ~

Co-Morbidity Effects

____ ___- ____ ____ ____

_____ _____
_____ ____ - ____
_____

Co-Morbidity Effects

Systemic disease - pancreatitis, diabetes, acromegaly

Radiation therapy

Drug induced - phenothiazines

Idiopathic