Immunologic Disorders

RESOURCE FACULTYDr. Jyotsna Rimal

Additional professor and HOD

Dr. Iccha kumar Maharjan

Associate professor

DEPARTMENT OF ORAL MEDICINE AND RADIOLOGY PRESENTER

Nabin Chaudhary

BDS 2011

Contents Immunodeficiency Primary immunodeficiencies

Deficiencies in innate immunity:phagocyte deficiencies

Deficiencies in adaptive immunity

T-cell deficiencies

B-cell deficiencies Secondary immunodeficiencies

Innate immune system Autoimmune disease

SLE

Scleroderma

Immunity

Acquired(specific) Innate(natural)

active passive

Natural:Follows clinical or subclinical infection

Artificial:Induced by vaccination Natural:

Transplacental passageof maternal IgG

Artificial:Injection of preformed antibody(e.g ATS)

Birds immune to tetanus;Algerian sheeps immune to anthrax

INNATE IMMUNITY Barriers

Physical

skinhairmucous

Chemicalsweat tearssalivastomach acidurine

Cells of innate immunity

Cells Location Function

Monocytes Blood Phagocytosis

Macrophages Tissue Phagocytosis, inflamation, Antigen presentation

Neutrophils Blood Phagocytosis

Eosinophils Tissue/blood Cytolysis

Basophils Blood Inflammation

Mast cells Tissue Inflammation

Natural killer cells Blood/Tissue Cytolysis

Dendritic cells Tissue Antigen presentation

Adaptive immune response

Third line of defense Precisely adapted to each specific microorganism encountered by an individual Memory Mounts rapid and efficient response in the next encounter Consists of Cells:

B lymphocytes T lymphocytes

Molecules: Antibodies, Cytokines

Primary:Thymus Bone marrow

Secondary:Payer’s patchSpleen Lymph node

ORGANS

Antibody

Two light chains (κ or λ)Two heavy chains (γ, α, μ,δ, ε)V: variable segmentC: constant segment

IgG

Major defence against bacteria and their toxin

% of total immuno-globulin

Functions

IgG 80 Complement activation, Major defence against bacteria and their toxin

IgA 13 Localized protection in external secretions (tears, intestinal secretions, etc)

IgM 6 Complement activation, Antigen recognition by B cells

IgD 0.1 Antigen recognition by B cells

IgE 0.002 Major defence against helminths; mediates allergic reation, releases histamine from basophils and mast cells

Immunity in Oral Cavity

Homeostasis in oral cavity is maintained by innate and acquired system in conjunction with normal oral flora and an intact oral mucosa.

Components contributing for oral defence: Mucosal integrity Major and minor salivary gland saliva Salivary innate microbial proteins Gingival crevicular fluid

Transudating plasma proteins

Circulating white blood cells

Oral mucosal keratinocyte products

Protein from microbial flora

IMMUNODEFICIES

PRIMARY IMMUNODEFECIENCY(<10%)• TCELL DEFECT• B CELL DEFECT• COMPLEMENT DEFECT• PHAGOCYTIC DEFECT

SECONDARY IMMUNODEFECIENCY(90%).DRUGS.INFECTIONS

Congenital Manifests since early age

Acquired Manifests at any ageResult either from production or destruction of immune cells orloss of components of humoral immunity

Immunodeficiency

T-cell deficiencies B-cell deficiencies

in T-cell number e.g.DiGeorge Syndrome(Velocardiofacial syndrome)

Qualitative T-cell defects e.g.Defects in MHC

in B-cell number e.g.Bruton’s X-linked Agammaglobulinemia and Non Bruton’s Agammaglobulinemia

in certain classes of immunoglobulins e.g. common variable immunodeficiency; selective immunoblobulin deficiency

Severe combined immunodeficiency(SCID)Wiskott Aldrich syndrome

Ataxia Telangiectasia

Oral complication with specific immunodeficiencies

Immune defect Disease example Common infectious susceptibility

Oral complications

Severe in neutrophil no.

Kostmann’s syndrome,Severe congenital neutropenia

Bacterial andFungal infections

Aggressive periodontitis,Recurrent oral ulcerations,Delayed wound healing,Candidiasis

Defective chemotaxis of neutrophils

Leukocyte adhesion deficiency

Bacterial andFungal infections

Aggressive periodontitis,Recurrent oral ulcerations,Delayed wound healing,candidiasis

Unknown Job’s syndrome Recurrent skin and mucous membrane infections

Delayed exfoliation of primary teeth,midline defects of tongue,oral candidiasis,characteristic face with broad nasal bridge

Severely T-and B-cell no.

SCID Infections of all types

Oral candidiasis,herpes,recurrent oral ulcerations,severe necrotizing gingival ulcerations

in T-cell no. DiGeorge syndrome

Recurrent viral and fungal infections

candidiasis,recurrent herpetic infections

Abnormal T-cell function

MHC class I deficiency of CD8 T-cellMHC class II deficiency of CD4 T-cell

Recurrent viral and fungal infections

candidiasis,recurrent herpetic infections

Severly B-cell no.

Bruton’s X-linked agammaglobulinemia

Recurrent respiratory and sinus infections

Possible sepsis from odontogenic infections

Solitary immunoglobulin class deficiency

Selective IgA deficiencySelective IgG deficiency

Varied from no symptoms to recurrent respiratory and sinus infections

Candidiasis,oral ulcerations,possible sepsis from odontogenic infections

Severe combined immunodeficiency

Immunocompromised;most die of infection before age of

1 year Types

1 adenosine deaminase deficiency

2 Mutation in Υc subunit of cytokine receptors

3 mutation in RAG1 or RAG2

4 mutation in CD3δ and CD3ε chains Treatment

Hematoietic stem cell transplantation(standard treatment)

Ex-vivo gene therapy

Aphthous like ulcerations Candidiasis Herpetic infections Severe necrotizing gingival

ulceration

Oral complication

Prof Ariyanto Harsono MD PhD SpA(K) 16

Wiskott Aldrich Syndrome

Oral manifestations Purpura Candidiasis Herpetic

infections

Characterised by triad of symptoms Microthrombocytopenia Eczema Immunodeficiency

Defect in WAS gene,which affects both T and B cells as well as platelets

C/FPetechie BruisingBloody diarrheaOtitis mediaPneumoniaSkin infections

17

Ocular and facial telangictases Sinopulmonary infections impaired organ maturation x-ray hypersensitivity predisposition to malignancy.

Ataxia-Telangictasia

C/F

Mutation of ATM geneDegenerative disorder characterized by cerebellar degeneration

Treatment Intravenous pooled immunoglobulin

18

DiGeorge Syndrome

Craniofacial features:Cleft palateBifid uvulaOral candidiasisShort palpebral fissuresSmall mouthProminent foreheadEnamel hypoplasiaAnterior glottic webs

Result from deletion of chromosome22q11.2;leading to failure of completedevelopment of thymus

TreatmentThymic transplantation

X-linked agammaglobulinemia(bruton’s Disease)

Mutation in the gene called bruton thyroid kinase(BTK)Virtual absence of B-cellsVery low level of all immunoglobulins( IgG, IgA, IgM, IgD and IgE)

Treatment

Aggressive antibiotic treatment and intravenous pooled immunoglobulin transfusions

Secondary immunodeficiencies

Cellular(primarily neutrophils) Neutropenia results during cancer chemotherapy, stem cell transplantation,aplastic

anemia and autoimmune neutropenia If ANC<1000cells/mm3 risk of nfection.Thus antibiotic prophylaxis should be given

prior to invasive dental procedures Complement Acquired deficiency seen in advanced liver disease Associted with increased incidence of bacterial infections and malignancies(CLL)

Innate immune system

Adaptive immune system

Decrease in T-cell no eg HIV and/or function eg chronic GVH disease,treatment with anti tumor necrosis(TNF-α)

Agents Infections with intracellular bacteria and fungi(pneumocystis

carinii),viruses(herpes family,papilloma virus) and parasites(Toxoplasma and cryptosporidium) are typical of T-cell-deficient states

Oral candidiasis(advanced HIV) Herpes zoster(CLL)

Homoral(antibodies)

• Associated with increased loss of immunoglobulin eg nephrotic syndrome• And decreased production of immunoglobulin eg multiple myeloma, CLL

Cell mediated

Case study Immunological investigations

Quantitative serum immunoglobulins (g/L):

IgG 0.17 (5.5–10.0)

IgA Not detected (0.3–0.8)

IgM 0.07 (0.4–1.8)

Antibody activity

Immunization responses – no detectable IgG antibodies to:

Tetanus toxoid (post Imx)

Haemophilus type b polysaccharides (post Imx)

Polio (post Imx)

Measles (post Imx)

Rubella (post Imx)

Isohaemagglutinins (IgM) not detected (blood group A Rh+)

Blood lymphocyte subpopulations (×109/L):

Total lymphocyte count 3.5 NR* (2.5–5.0)

T lymphocytes (CD3) 3.02 NR (1.5–3.0)

B lymphocytes (CD19) <0.1 NR (0.3–1.0)

Peter was born after an uneventful pregnancy. At 3 months, he developed otitis media At the ages of 5 months and 11 months, he

was admitted to hospital with untypable Haemophilus influenzae pneumonia.

He is the fourth child of unrelated parents;his three sisters showed no predisposition to infection.

All immunizations were uneventful. severe reduction in all three classes

of serum immunoglobulins and no specific antibody production

mutation in the Btk gene was detected

Diagnosis???

Bruton’s disease(X-linked agammaglobulinaemia) Treated by 2-weekly intravenous infusions of

human normal IgG in a dose of 400 mg/kg body weight/month.

McQ Which of the following Ig is involved in mediating allergic reactions a) IgG b) IgM c) IgE d) IgA

All of the following are autoimmune disorders except a) Graves disease b) SCID c) Rheumatoid arthritis d) Addison’s disease

(b)

(c)

Systemic lupus erythematosus

Autoimmune disorder characterized by multisystem microvascular inflammation with the generation of autoantibodies

When the skin is involved- lupus dermatitis or cutaneous lupus erythematosus.

isolated to the skin, without internal disease- discoid lupus.

internal organs are involved-systemic lupus erythematosus (SLE)

Etiology and pathogenesis ____________________

Genetic Environmental

Though etiology is unknown

Progressive loss of tolerance

Production of autoantibodies

ManifestationsCVSLungKidney(Renal)MusculoskeletalCNSothers

American college of Rheumatology criteria

MALAR RASH

DISCOID RASH

PHOTOSENSITIVITY

ORAL ULCERS

ARTHRITIS

SEROSITIS

RENAL DISORDER

NEUROLOGIC DISORDER

HEMATOLOGICAL DISORDER

IMMUNOLOGIC DISORDER

ANTINUCLEAR ANTIBODY

If ≥4 of these criteria,are present diagnosis likely to be SLE ;sensentivity=70-96%;specificity=90-100%

Antibody Prevalence(%) Clinical utility

Antinuclear antibodies 98 Best screening test; repeated negative tests make SLE unlikely

Anti-dsDNA 50-60 Highly specific

Anti-Sm 25 Specific for SLE

Anti-RNP 40 Not specific for SLE

Anti-Ro (SS-A) 25-40 Not specific for SLE;associated with sjogren’s Syndrome,linked to subacute cutaneous lupus and neonatal attack

Anti-La (SS-B) 10-15 Not specific for SLE;associated with sjogren’s syndrome

Laboratory investigations

Antihistone 70 More frequent in drug-induced lupus than in SLE

Antiphospholipid 50Three tests available— ELISA s for cardiolipin and 2G1, sensitive prothrombin time (DRVVT); predisposes to clotting, fetal loss, thrombocytopenia 

Antierythrocyte 60 Measured as direct Coombs' test; a small proportion develops overt hemolysis

Antiplatelet 30 Associated with thrombocytopenia but sensitivity and specificity are not good; this is not a useful clinical test

Antineuronal (includes anti-glutamate receptor)

60 In some series a positive test in CSF correlates with active CNS lupus

Antiribosomal P 20 correlates with depression or psychosis due to CNS lupus

Immunohistology:

Direct Immunofluorescence

Lupus band test:

-Deposition of IgG;IgM and C3 in a band like pattern at the dermo-epidermal junction.

Oral manifestations Site:buccal mucosa,lip,palate,gingiva Symptoms:complains of burning

Sensation,xerostomia,soreness of mouth Characteristically painless Whitish striae radiating from central erythematous area,giving so

called ‘brush border’ Lip lesion: central atrophic & occasionally ulcerated area

with small white dots surrounded by keratinized border composed of small radiating white striae.

INTRA ORAL LESION: composed of a central depressed red atrophic area surrounded by 2-4 mm elevated keratotic zone that dissolve into a white line.

Dental Management Risk of infection:

• Complete blood count

• If ANC<1000 cells/mm3;elective oral surgical procedures with potential for bacteremia should be delayed

• Antibiotic prophylaxis often recommended

Risk of bleeding

Platelet transfusions recommended in surgical patients with platelet count<50,000/mm3

controlled by local measures such as pressure and application of hemostatic agents,

platelet transfusion can be performed postoperatively if bleeding occurs despite local measures

Oral surgical procedures are safe with INR=2-3.5 and do not require discontinuation of anticoagulants

Adrenal suppression

Any patients with supraphysiologic corticosteroids intake for 2 weeks or longer in 2years time is at risk of adrenal suppression

Adrenal insufficiency:corticosteroid supplementation

Dental surgical procedures Previous systemic steroid use Current systemic steroid use

Minor oral surgery lasting <1 hr with local anesthetic only

Consider supplementation with 25mg of hydrocortisone equivalent before surgery;esp. if patient is infected

Consider supplementation with 25mg of hydrocortisone equivalent before surgery;esp. if patient is infected.No need to supplement if the patient is taking over 50mg hydrocortisone equivalent daily

Oral surgery with or without GA lasting >1 hr

Major oral surgery with GA lasting >1 hr and having significant blood loss,such as cancer or orthognathic surgery

50-100mg of hydrocortisone equivalent the day of surgery,with continuation of the dose for an additional day on the amount of

blood loss,presence of infection and length of surgery

Usual daily dose before surgery and hydrocortisone equivalent of 5o mg hydrocortisone IV during surgey and every 8hr after initial

dose for upto 72hr

Treatment Medications Dose

NSAIDS Doses toward upper limit of recommended range

Topical glucocorticoids 0.05%betamethasone dipropionate bd local application x 2weeks followed by 2weeks rest period

Topical sunscreens SPF 15 at least;30+preferred

hydroxychloroquine 200-400 mg/day

DHEA(dehydroepiandrosterone) 200mg/day

Methotrexate b(for dermatitis,arthritis) 10-25 mg once a week,po or sc with folic acid;decrease dose if CrCl<60mL/min

Glucocorticoids oral Prednisolone:0.5-1 mg/kg per day for severe SLE0.07-0.3 mg/kg per day or qod for mild SLE

Methylprednisolone sodium succinate iv For severe dz;1g iv/day x 3days

cyclophosphamide IV 7-25 mg/kg /month x 6month;consider mesna administration with dose;1.5-3 mg/kg per day(decrease dose for CrCl<25ml/min)

Mycophenolate mofetil 2-3g/d PO(decrease dose if CrCl<25mL/min)

Azathioprine 2-3mg/kg per day PO(decrease frequency of dose if CrCl<50mL/min)

Scleroderma

Chronic disease characterised by

- thickening and fibrosis of skin Systemic sclerosis:fibrosis extends to internal

organs including heart,lungs,kidney,and GI tractTypes A) localized form i) linear ii) morphea B) progressive systemic sclerosis i) limited cutaneous scleroderma ii) diffuse cutaneous scleroderma

En coup de sabre

Morphea

Etiology and pathogenesis

Etiology is unclear Genetic predisposition Environmental exposure to pesticides,benzene derivatives,silica Viral triggers such as parvovirus B19 Pathogenesis is characterized by vascular damage Unregulated collagen deposition is a hallmark of disease

Clinical features

Raynaud’s phenomenon Cutaneous manifestations Musculoskeletal manifestations GI manifestations Cardiac manifestations Pulmonary manifestations Renal manifestations

Lab investigations• ANA(>90%patients)• Anticentromere(ACA)• AntitopoisomeraseI(Anti topo I)• Anti RNA polymerase I/III• Anti Th/To2-36

Oral manifestations

Difficulty in opening mouth and loss of tongue movement due to perioral and lingual fibrosis

Lips become thin, rigid & fixed producing microstomia

Maxillary anterior teeth are exposed due to retraction of lips

Masklike appearace to face Tongue becomes hard and rigid

causing difficulty in speaking and swallowing.

Reduce salivary flow rate(due to medications)

Gingival hyperplasia(due to CCB)

Loss of taste, pemphigus,bood dyscrasias lichenoid reaction(due to penicillamine)

Classic radiographic finding is generalized uniform widening of periodontal ligament space(2-4 times)

Bone resorption at the angle of mandible,condylar heads,coronoid process or digastric region(when fibrosis involves muscles of mastication)

Dental aspect Physical limitation caused by narrowing of oral aperture and

rigidity of tongue Poor oral hygiene;caries and plaque associated with decreasing

dexterity Dental procedures(molar endodontics,prosthetics,restoration in

posterior regions)become difficult Dental treatment altered due to physical problem of access Mouth stretch exercises No. of tongue blades increased between posterior teeth to

stretch facial muscles B/L commissurotomy

management

Non-pharmacological:

- Take warm water bath

- Avoid cold contact ( Especially in winters)

- Wear woolen gloves and socks

- Smoking and drugs like B-blocker inducing vasospasm is strictly prohibited

Pharmacological CCB, Nifedipine(30-90mg/day), non responsive once can use

Nicardipine(30-60mgbid) Combination of Pentoxifylline(400mg bid) and low dose aspirin(75

mg/day). Pentoxifylline improves digital perfusion by increasing the deformability of RBC plasma membrane

Immunomodulators: cyclosporine, methotrexate.

Antifibrotic therapy: D-PENICILLAMINE(start with 125-250mg OD then 250mg BD)

INFά & INFγ.

Case studyA 26-year-old woman presented with fatigue and painful, stiff knees of 4 weeks’ duration. She had a 6-year history

of raynaud’s phenomenon, frequent mouth ulcers and had had a blotchy rash

Bilateral effusions in both knee joints, but all other joints were normal.

She had no skin lesions, muscle tenderness, proteinuria or fever.

Full blood count showed mild thrombocytopenia and lymphopenia

InvestigationsC-reactive protein 8 mg/l (normal)Rheumatoid factor NegativeAntinuclear antibody PositiveAnti dsDNA-antibodies 80 (<25)

Serum complement levels C3 0.35 g/l (NR 0.65–1.30) C4 0.05 g/l (NR 0.20–0.50)

Serum immunoglobulins IgG 22.0 g/l (NR 7.2–19.0) IgA 3.8 g/l (NR 2.0–5.0) IgM 1.2 g/l (NR 0.5–2.0)Biopsy of normal, sun-exposed skin (lupus band test) Granular deposits of IgG and complement at dermo–epidermal junction Lupus band test

Well-demarcated digital ischaemia due to Raynaud’s phenomenon

Blotchy erythema on the dorsum of the hands

Diagnosis???

SLE treated with aspirin for her painful knees Following treatment with hydroxychloroquine, the

skin manifestations gradually disappeared

Revision

American college of rheumatology criteria for SLE Corticosteroids supplementation Most sensitive diagnostic test for SLE= CREST syndrome Most common problem associated with scleroderma for

dental procedures= Longest life which immunoglobulin= Immunoglobulin in secretions=

ANA

Trismus

IgG

IgA

McQ

In severe combined immune deficiency (SCID), the patients are deficient in

a) B cells

b) T cells

c) both a and b

d) IgA

SCID can occur due to the absence of an enzyme

a) adenosine deaminase

b) guanosine deaminase

c) phosphorylase

d) thymidine deaminase

(c)

(a)

All of the following are immunodeficiency diseases except

a) Graves disease

b) SCID

c) DiGeorge’s syndrome

d) Hyper IgE syndrome

Some defects or mutations in components of innate or adaptive immunity may lead to

a) hypersensitivity

b) auto-immune diseases

c) immunodeficiency

d) tolerance

(c)

(a)

References

Burkit’s Oral Medicine 11th edition

Textbook of oral medicine,2nd edition,Anil Ghom

A textbook of microbiology p. Chakraborty

Understanding medical physiology RL Bijlani 4th edition

McGraw-Hill’s access medicine

Essentials of Clinical Immunology, Sixth Edition. Helen Chapel, Mansel Haeney, Siraj Misbah, and Neil Snowden.© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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