Immunological disease

Immunological DiseaseDisease

Dr. Deepak K. Gupta

Syllabus

• Immuno deficiency disorders– a brief knowledge of various types of immuno deficiency

disorders– A sound knowledge of immunodeficiency disorders

relevant to dentistry.

• Hypersensitivity reactions • Hypersensitivity reactions • Autoimmune disorders

– Basic knowledge of various types– sound knowledge of autoimmune disorders of oral cavity

and related structure

• Immunology of Transplantation and Malignancy • Immunehaematology

Immunodeficiency disordersImmunodeficiency disorders

Introduction

• A state in which the immune system's ability to fight infectious disease is compromised or entirely absent.

• It may be 2 types• It may be 2 types– Primary: Usually congenital, resulting from genetic

defects in some components of the immune system.

– Secondary (Acquired): as a result of otherdiseases or conditions such as HIV infection,malnutrition, immunosuppression

Primary Immunodeficiency Disease• Myeloid lineage

– Congenital agranulocytosis

– Leukocyte-adhesion deficiency

• Lymphoid lineage

– Severe combined immunodeficiency (SCID)

– B cellsAgammaglobulinemia• Agammaglobulinemia

• Hypogammaglobulinemia

• Specific Ig Deficiencies

– T cells• DiGeorge Syndrome

• Wiskott Aldrich Syndrome

• Complement system deficiency

• Disorder of Phagocytosis : chronic granulomatous disease

Symptoms

• Recurrent respiratory infections.

• Persistent bacterial infections →sinusitis, otitis and bronchitis.

• Increased susceptibility to opportunistic infections (OIs) and recurrent fungal yeast infections.and recurrent fungal yeast infections.

• Skin and mucous membrane infections.

• Resistant thrush, oral ulcers and conjunctivitis.

• Diarrhoea and malabsorption.

• Failure to thrive and delayed or incomplete recovery from illness.

Aetiology• Aetiology associated with

– Genetic defects of missing enzymes.

– Specific development impairment (pre-B-cell failure). cell failure).

– Infections, malnutrition and drugs

Severe combined immunodeficiency (SCID)

• Various genetic defects

• No TCR or defective TCR

• Defective cell signaling

• Defective IL 2• Defective IL 2

• Recurrent infections

• Death at early age

Secondary Immunodeficiency

• Drug related

• Disease related

– Cancer

– AIDS– AIDS

• HIV

• T helper cell as target

Acquired Immunodeficiency Syndrome/AIDSSyndrome/AIDS

Introduction

• Caused by Human

Immunodeficiency

Virus (HIV)

• Human immune • Human immune

system are unable to

overcome the

infection.

• The person becomes

“immunodeficient”

Introduction

• A weak immune system can no longer effectively

defend the body resulting to

– The body becomes vulnerable to a variety of infections &

cancers.cancers.

– Infections that take advantage of a weakened immune

system are “opportunistic infections”.

– Eventually the immune system is so weak that the body is

overwhelmed by infections and/or cancers, and the person

dies.

Acquired Immunodeficiency Syndrome (AIDS)

• A “syndrome” is a group of symptoms & signs associated with the same underlying condition.

• Classified in 2-type• Classified in 2-type

– HIV-1: predominantly found in East, Central, South Africa and other parts of the world

– HIV-2 reported mainly in W. Africa.

PREVALENCE

• HIV infection – global pandemic• Worldwide 40.3 million infected people,

– Among adults 15 - 49 yrs. , 1.1%

– 4.1 million death– 4.5 million new cases/ year– 4.5 million new cases/ year– 14,000 new infections/ day

• 2.40 million Indians are living with HIV– 83% are the in age group 15-49 years– 39% (930,000) are among women– Andhra Pradesh, Maharashtra, Karnataka , Tamil Nadu – account

for 55%

– (UNAIDS 2006 )

History

• 1979 – Increased Kaposi sarcoma and Pneumocystis carinii infections in homosexuals noted in Africa.

• 1981 – First case in California.• 1981 – First case in California.

• > 30 million in world – 1999 – increasing

HIV VIROLOGY

• It is RNA virus, in the group of lenti virus.

– Subfamily of retrovirus.

• It contains two copies of single stranded Ribonucleic Acid (RNA).

• Viral RNA is surrounded by a capsid made from viral • Viral RNA is surrounded by a capsid made from viral proteins

• This is enclosed in a viral envelope formed from the cellular membrane of the host cell.

• Primary targets CD4+T lymphocytes

• Over time, CD4 cell counts decline and results in a poorly functioning immune system

HIV VIROLOGY

HIV Pathophysiology

• Penetration of virus in tohost plasma membrane results into virion

• Reverse transcriptase and integrase molecules get attached to viral RNA. attached to viral RNA.

• These helps in the synthesizes of DNA copies of RNA. – Integrase catalyses

their insertion into the host DNA chromosome in the nucleus.

TransmissionIt can be transmitted through the following body fluids:• Blood• Semen• Vaginal fluid• Breast milkHIV can’t be transmitted through the following :HIV can’t be transmitted through the following :• Saliva• Tears• Urine• Mosquitoes• Toilet Seats• Kissing• Hugging

Concentration in Human Body FluidsConcentration in Human Body Fluids

Blood

Semen

Milk

Saliva

Vaginal secretion

CLASSIFICATION

CLASSIFICATION

• CDC classifies HIV infection into 3 categories, as follows :– Category A: Asymptomatic HIV infection without a

history of symptoms or AIDS-defining conditions

Category B: HIV infection with symptoms that are – Category B: HIV infection with symptoms that are directly attributable to HIV infection (or a defect in T-cell–mediated immunity) or that are complicated by HIV infection

– Category C: HIV infection with AIDS-defining opportunistic infections

CLASSIFICATION

• These 3 categories are further subdivided on the basis of the CD4+ T-cell count, as follows:

1. > 500/µL: Categories A1, B1, C1

2. 200-400/µL: Categories A2, B2, C22. 200-400/µL: Categories A2, B2, C2

3. < 200/µL: Categories A3, B3, C3

SIGNS AND SYMPTOMS

• The patient with HIV may present with signs and symptoms of any of the stages of HIV infection.

• No physical findings are specific to HIV infection; • The physical findings are those of the presenting infection

or illness.• Manifestations include the following:• Manifestations include the following:

– Acute seroconversion manifests as a flulike illness, consisting of fever, malaise, and a generalized rash

– The asymptomatic phase is generally benign– Generalized lymphadenopathy is common and may be a

presenting symptom– Recurrent, severe, and occasionally life-threatening infections or

opportunistic malignancies

SIGNS AND SYMPTOMS

• HIV infection can cause some sequelae,

• Including AIDS-associated dementia/encephalopathy

• HIV wasting syndrome • HIV wasting syndrome (chronic diarrhea and weight loss with no identifiable cause)

SIGNS AND SYMPTOMS

HIV Screening & Diagnosis

• Antibody detection:– Blood donors screening,– ELISA, Western-Blot (Confirmatory)

• Antigen detection– Blood donors screening, diagnostic– Blood donors screening, diagnostic– ELISA

• Nucleic Acid Testing (DNA, RNA):– Blood donors screening (on pools), diagnostic, follow up– Lymphocyte culture

• Tests for defects in immunity• CD4+ T cell counts

Oral Manifestation of HIV

• Oral conditions associated with HIV infection are divided into five major groups:

-Microbiological infections (fungal, bacterial, viral)

-Oral neoplasias

-Neurological conditions

-Lesions of uncertain aetiology-Lesions of uncertain aetiology

-Oral conditions associated with HIV treatment.

• Other co-infections and conditions associated with HIV infection, which are significant to dentists are:

-Syphilis

-Tuberculosis

-Persistent generalised lymphadenopathy

-Gastro-oesophageal reflux disease (GORD).

TREATMENT

• Highly active antiretroviral therapy (HAART) is the principal method for preventing immune deterioration.

• Classes of antiretroviral agents include the following:– Nucleoside reverse transcriptase inhibitors (NRTIs)

– Protease inhibitors (PIs)– Protease inhibitors (PIs)

– Nonnucleoside reverse transcriptase inhibitors (NNRTIs)

– Fusion inhibitors

– CCR5 co-receptor antagonists (entry inhibitors)

– HIV integrase strand transfer inhibitors

Hypersensitivity reactions

An exaggerated or inappropriate state of An exaggerated or inappropriate state of normal immune response with onset of

adverse effects on the body

Hypersensitivity reactions

• The lesions of hypersensitivity are a form of antigen - antibody reaction.

• Subdivided into four types;– Type I hypersensitivity

– Type II hypersensitivity

– Type III hypersensitivity

– Type IV hypersensitivity

• First three are variations on antibody-mediated (Immediate type) injury, whereas the fourth is cell mediated (delayed type)

TYPE I HYPERSENSITIVITY

• A state of rapidly developing or anaphylactic type of immune response to an antigen (i.e. allergen) to antigen (i.e. allergen) to which the individual is previously sensitised.

• The reaction appears within 15-30 minutes of exposure to antigen

TYPE I HYPERSENSITIVITY

• First contact of the host with the antigen, sensitisation takes place.

• In response to initial contact with antigen, circulating B lymphocytes get activated

• And it differentiate to form IgE-secreting plasma cells.plasma cells.

• IgE antibodies so formed bind to the Fcreceptors present on the surface of mast cells and basophils

• During the second contact with the same antigen

• The combination sets in cell damage

– Membrane lysis,

– Influx of sodium and water

– degranulation of mast cells-basophils

Clinical and Pathologic Manifestations

• Generalized manifestation– Itching, urticaria (hives), and skin erythema– Followed in short order by profound respiratory difficulty

• Pulmonary bronchoconstriction• Accentuated by hypersecretion of mucus.

– Laryngeal edema may cause upper airway obstruction– Musculature of the entire gastrointestinal tract – Musculature of the entire gastrointestinal tract

• Resultant vomiting• Abdominal cramps• Diarrhea

– systemic vasodilation with fall in blood pressure– may progress to circulatory collapse and death within minutes

• Local reactions– Skin (contact, causing urticaria),– Gastrointestinal tract (ingestion, causing diarrhea)– Lung (inhalation, causing bronchoconstriction)

Clinical and Pathologic Manifestations

• Systemic anaphylaxis– Administration of antisera e.g. anti-tetanus serum (ATS)

– Administration of drugs e.g. penicillin

– Sting by wasp or bee

• Local anaphylaxis• Local anaphylaxis– Hay fever: pollen

– Bronchial asthma

– Food allergy to ingested allergens like fish, cow’s milk, eggs etc.

– Cutaneous anaphylaxis

– Angioedema

Hypersensitivity Type II

TYPE II HYPERSENSITIVITY

• Cytotoxic type reaction

• Reactions by humoral antibodies that attack cell surface antigens on the specific cells and tissues and cause lysis of target cellstissues and cause lysis of target cells

• Within 15-30 minutes after exposure to antigen

ETIOLOGY AND PATHOGENESIS

• Participation by complement system,

• Tissue macrophages, platelets, natural killer cells, neutrophils and eosinophils

• Main antibodies are IgG and IgM• Main antibodies are IgG and IgM

Clinical Manifestation

• Cytotoxic antibodies to blood cells– Autoimmune haemolytic anaemia– Transfusion reactions– Haemolytic disease of the newborn (erythroblastosis foetalis)– Idiopathic thrombocytopenic purpura (ITP)– Leucopenia with agranulocytosis– Leucopenia with agranulocytosis– Drug-induced cytotoxic antibodies

• Cytotoxic antibodies to tissue components– Graves’ disease– Myasthenia gravis– Male sterility– Type 1 diabetes mellitus– Hyperacute rejection reaction

Hypersensitivity Type III

Type III hypersensitivity is also known as immune complex hypersensitivity.

The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction).

The reaction may be general (e.g., serum sickness) or

Type III (ICM) Hypersensitivity

The reaction may be general (e.g., serum sickness) or may involve individual organs including or other organs.

Antigens causing immune complex mediated injury are:

Exogenous

Endogenous

Mechanism of Type III Hypersensitivity

Antigens combines with antibody within circulation and form immune complex

Wherever in the body they deposited

They activate complement system


They activate complement system

Polymorphonuclear cells are attracted to the site

Result in inflammation and tissue injury

Pathogenesis of TYPE III

Antigens combine with antibodies to formantigen-antibody complexes.

Antigen

Antibody (IgG)

Antigen-antibody complex

Phagocytes remove mostof the complexes, butsome lodge in the wallsof blood vessels.

There the complexesactivate complement.

Inactive complementTYPE III Hypersensitivity

Inactive complement

Active complement

Antigen-antibody complexesand activated complementattract and activateneutrophils, which releaseinflammatory chemicals.

Neutrophil

Inflammatory chemicals

Inflammatory chemicalsdamage underlyingblood vessel wall.


Hypersensitivity Type III Reactions

Systemic ReactionsLocal Reactions

Arthus Reaction:

It is named for Dr. Arthus.

Inflammation caused by the deposition of immune complexes at a localized site.

Clinical Manifestation is :Hypersensitivity Pneumonitis

Serum Sickness:

Systemic inflammatory response to deposited immune complexes at many areas of body.

Few days to 2 weeks after injection of foreign serum or drug it results in :Fever, Urticaria, Artheralgia, Eosinophila, Spleenomegally, and Lymph adenopathy

Immune Complex Diseases:

Hypersensitivity Pneumonitis

Glomerulonephritis

Type III Hypersensitivity: Clinical Manifestation

Glomerulonephritis

Rheumatoid Arthritis

Systemic Lupus Erythematosus

Hypersensitivity pneumonitis

Inhalation of antigens into lungs stimulates antibody production


Subsequent inhalation of the same antigen results in formation of immune complexes

» Activates complement

Glomerulonephritis

Immune complexes in the blood are deposited in glomeruli

Damage to the glomerular cells impedes blood


Damage to the glomerular cells impedes blood filtration

Kidney failure and, ultimately, death result

Rheumatoid arthritis

Immune complexes deposited in the joint

» Results in release of inflammatory chemicals

» The joints begin to break down and become


» The joints begin to break down and become distorted

Trigger not well understood

Treated with anti-inflammatory drugs

The crippling distortion of joints characteristic of rheumatoid arthritis

Systemic lupus erythematosus

Autoantibodies against DNA result in immune complex formation

Many other autoantibodies can also occur


Many other autoantibodies can also occur

» Against red blood cells, platelets, lymphocytes, muscle cells

Trigger unknown

Immunosuppressive drugs reduce autoantibody formation

Glucocorticoids reduce inflammation

The characteristic facial rash of systemic lupus erythematosus

Hypersensitivity Type IV

Delayed hypersensitivity is a function of T Lymphocytes, not antibody.

It starts hours (or Days) after contact with the antigen and often lasts for days.

Principal pattern of immunologic response to variety of intra cellular microbiologic agents

i.e.: Mycobacterium Tuberculosis

Viruses

Type IV (Cell Mediated) Hypersensitivity

Viruses

Fungi

Parasites

Mechanism

• Activation of T Lymphocytes

• Release of cytokines and macrophage activation

• T-cell mediated cytotoxicity

The tuberculin response

• An injection of tuberculin beneath the skin causes reaction in individual exposed to tuberculosis or tuberculosis vaccine

Type IV Hypersensitivity: Clinical Manifestation

• Used to diagnose contact with antigens of M. tuberculosis

» No response when individual not infected or vaccinated

» Red, hard swelling develops in individuals previously infected or immunized

A positive tuberculin test

Allergic contact dermatitis

• Cell-mediated immune response

• Results in an intensely irritating skin rash


• Triggered by chemically modified skin proteins that the

body regards as foreign

• Acellular, fluid-filled blisters develop in severe cases

• Can be treated with glucocorticoids

Allergic contact dermatitis

Graft rejection

• Rejection of tissues or organs that have been transplanted

• Grafts perceived as foreign by a recipient undergo rejection


rejection

• Immune response against foreign MHC on graft cells

• Rejection depends on degree to which the graft is foreign to the recipient

» Based on the type of graft

Types of grafts

Autograft

Isograft Allograft Xenograft

Genetically identicalsibling or clone

Genetically differentmember of same species

Summary

Auto-immune Disease

The state in which the body’s immune systemThe state in which the body’s immune systemfails to distinguish between ‘self’ and ‘non-self’ and reacts by formation of autoantibodies against own

tissue.

Auto-immune Disease

• Theories of Autoimmunity– Immunological factors– Genetic factors

• increased expression of Class II HLA antigens• Evidence from increased familial incidence• Evidence from increased familial incidence

– Microbial factors• Infection with microorganisms, particularly viruses (e.g. EBV

infection), and less often bacteria (e.g. streptococci, Klebsiella) and mycoplasma

• Types of Autoimmunity– Organ Specific– Organ non-specific

ORGAN NON-SPECIFIC - SYSTEMIC

• Systemic lupus erythematosus

• Rheumatoid arthritis

• Scleroderma (Progressive systemic sclerosis)

• Polymyositis-dermatomyositis• Polymyositis-dermatomyositis

• Polyarteritis nodosa (PAN)

• Sjögren’s syndrome

• Reiter’s syndrome

• Wegener’s granulomatosis

ORGAN SPECIFIC - LOCALISED• ENDOCRINE GLANDS

– Hashimoto’s (autoimmune) thyroiditis

– Graves’ disease

– Type 1 diabetes mellitus

– Idiopathic Addison’s

• BLOOD CELLs

– Autoimmune haemolyticanaemia

– Autoimmune thrombocytopenia

– Pernicious anaemia– Idiopathic Addison’s disease

• ALIMENTARY TRACT– Autoimmune atrophic

gastritis in pernicious anaemia

– Ulcerative colitis

– Crohn’s disease

– Pernicious anaemia

• OTHERS

– Myasthenia gravis

– Goodpasture’s syndrome

– Primary biliary cirrhosis

– Lupoid hepatitis

– Membranous glomerulonephritis

Systemic Lupus Erythematosus (SLE)

• Classical example of systemic autoimmune orcollagen diseases

• 2 forms of lupus erythematosus• Systemic or disseminated form

– Acute and chronic inflammatory lesions widely scattered in the bodybody

– Presence of various nuclear and cytoplasmic autoantibodies in the plasma

• Discoid form– chronic and localised skin lesions – involving the bridge of nose and adjacent cheeks– Without any systemic manifestations.– Rarely, discoid form may develop into disseminated form.



Scleroderma (Progressive Systemic Sclerosis)

• Skin disease characterised by progressive fibrosis

• 2 main types

• Diffuse scleroderma• Diffuse scleroderma– Skin shows

widespread involvement

– May progress to involve visceral structures

• CREST syndrome

Scleroderma-Diffuse scleroderma

Sjogren’s syndrome

• Sicca syndrome

• Gougerot-sjorgen syndrome

• Triad

– Keratonjuctivitis sicca– Keratonjuctivitis sicca

– Xerostomia

– Rheumatoid arthritis

• Along with SLE, polyarthritis nodosa, polymyositis or scleroderma

Primary Sjorgen’s syndrome or SICCA complex

Secondary Sjorgen’s Syndrome

Clinical features

• 0.5-1% of population

• Female >40 yrs, F:M = 10:1

• Children or young may be affected

• Dryness of mouth and eyes – hypofunction of • Dryness of mouth and eyes – hypofunction of salivary gland and lacrimal glands

• Painful, burning sensation of oral mucosa

• Nose, larynx, pharynx, tracheobronchial tree and vagina additionally involved

Clinical presentation• Oral mucosa

– Parchment like appearance –red, dry, tendered, smooth glazed

– Difficulty in wearing dentures

• Saliva – frothy• Angular cheilitis• Angular cheilitis• Disturbances of taste senation• Recurrent candidiasis –

dorsum of tongue – red & atrophic mucosa – fissuring and labulations on surface (COBBLE-STONE)

• Acute bacterial sialadenitis

Radiographic features• Sialography

– Punctate– Cavitary defect – filled

with radioopaquecontrast media

• ‘Cherry blossom’ or ‘branchless fruit laden ‘branchless fruit laden tree’

– Contrast media extravasates through weakened salivary gland

– Poor elimination of contrast media – over a month

Treatment• No satisfactory t/t• SYMPTOMATICALLY treated• Keratoconjuctivitis

– Occular lubricant – artificial tears like methyl cellulose

• Xerostomia• Xerostomia– Salivary subsitute

• Extensive dental caries• Fluoridation and oral prophylaxis is indicated

• Surgery not indicated unless the disease is cause discomfort to p/t

• Radiotherapy – not recommended

HLA complex

• Human Leucocyte Antigens

• Determine one’s own tissue from non-self- histocompatibility

• Immense importance so they are called • Immense importance so they are called major histocompatibility complex (MHC) or HLA complex

• Most of MHC are located on a portion of chromosome 6 of all nucleated cells of the body and platelets

HLA complex• Class I MHC antigens

– HLA-A, HLA-B and HLA-C

– CD8+ i.e. T suppressor lymphocytes carry receptors for class I MHC

• Class II MHC antigens: HLA-• Class II MHC antigens: HLA-D

• Class III MHC antigens: complement system (C2 and C4) coded on HLA complex• not associated with HLA

expression

Clinical Importance: HLA complex

• Organ transplantation

• Regulation of the immune system– Class I: function of cytotoxic T cells (CD8+ subpopulation)

– Class II: function of helper T cells (CD4+ subpopulation).

• Association of diseases• Association of diseases– Inflammatory disorders e.g. ankylosing spondylitis.

– Autoimmune disorders e.g. rheumatoid arthritis, insulin dependent diabetes mellitus.

– Inherited disorders of metabolism e.g. idiopathichaemochromatosis

Transplant Rejection

• According to the genetic relationship between donor and recipient, transplantation of tissues is classified into 4 groups:

– Autografts: donor and recipient is the same individual

– Isografts: donor and recipient of the same genotype.– Isografts: donor and recipient of the same genotype.

– Allografts: donor is of same species but of a different genotype.

– Xenografts: donor is of a different species from that of the recipient

• For transplant to be successful there must be matching of HLA complex

Transplant Rejection

• The greater the genetic disparity between donor and recipient in HLA system - stronger and more rapid will be the rejection reaction

• Besides the rejection reaction, a peculiar problem occurring especially in bone marrow transplantation is Graft-versus-host (GVH) reactionhost (GVH) reaction– Fever,– Weight loss & anaemia– Dermatitis, – Diarrhoea,– Intestinal malabsorption– Pneumonia– Hepatosplenomegaly

Mechanisms of Graft Rejection

• Except for autografts and isografts, an immune response against allografts is inevitable.

• Immunosuppressive drugs: survival of allograftsin recipients possible.

• Rejection of allografts involves both cell-• Rejection of allografts involves both cell-mediated and humoral immunity.

• Types of Rejection Reactions– Hyperacute rejection– Acute rejection– Chronic rejection

HYPERACUTE REJECTION

• Within minutes to hours of placing the transplant and destroys it.

• Humoral antibody against donor-antigen

• Cross-matching of the donor’s lymphocytes with • Cross-matching of the donor’s lymphocytes with those of the recipient before transplantation-reduced the frequency of hyperacute rejection.

• Organ becomes swollen, oedematous, haemorrhagic, purple and cyanotic rather than gaining pink colour.

ACUTE REJECTION

• Within a few days to a few months of transplantation

• It may be

– Acute humoral rejection: Extensive infiltration of lymphocytes (mainly T cells), a few plasma cells, monocytes and a few polymorphspolymorphs

• damage to the blood vessels and there are foci of necrosis in the transplanted tissue

– Acute cellular rejection• Poor response to immunosuppressive therapy,

• Acute rejection vasculitis and foci of necrosis in small vessels

CHRONIC REJECTION

• Repeated attacks of acute rejection

• May develop slowly over a period of months to a year

• Immunologic or ischaemic• Immunologic or ischaemic

• Ex: Renal transplant - rising serum creatininelevels– intimal fibrosis

– interstitial fibrosis and tubular atrophy

– may develop glomerulonephritis

Health & Medicine

Immunological disease