T CELL-MEDIATED HYPERSENSITIVITY(TYPE IV)

DR. HASNI MAHAYIDIN (hasnim_7@yahoo.com)IMMUNOLOGY UNITPATHOLOGY DEPARTMENTFACULTY OF MEDICINE AND HEALTH SCIENCESUNIVERSITI PUTRA MALAYSIA

RECAP•Hypersensitivity reaction:

▫Excessive / inappropriate immune response

RECAP•Classification of hypersensitivity:

▫Coombs and Gell (1963)

TYPES IMMUNE COMPONENT

CLINICAL

I (immediate) IgE, mast cells, eosinophils

Allergic reactions

II Antibodies (IgG, IgM)

Antibody-mediated cell reactions

III Antibodies Immune complex-mediated reactions

IV T cells Cell-mediated reactions

T cell-mediated immune response

Immunity

Innate

Adaptive

Humoral

Cell- mediate

d

Type IV hypersensitivity•aka:

▫Delayed-type hypersensitivity (DTH)▫T cell-mediated hypersensitivity▫Cellular-mediated hypersensitivity

•T cell-mediated inflammatory response

T cell-mediated HS•Involved antigen specific CD4+ T cells•CD4+ T cells are normal component of

adaptive immunity•Essential for control of pathogens,

particularly intracellular organisms•May also response to chemicals and self

antigens•However, if the response is excessive

damage to host

•2-phase:▫Sensitization phase▫Effector phase

•>12hrs to develop (according to the Coombs and Gell classification)

•Three variants of DTH:▫Contact Hypersensitivity▫Tuberculin-type Hypersensitivity▫Granulomatous Hypersensitivity

•The 3 types of DTH were originally distinguished according to the reaction they produced when the antigen was directly applied to the skin (epicutaneously) or injected intradermally.

•The degree of response is usually assessed by measuring thickening of the skin.

Phases of DTH• Primary contact

• Sensitization (1-2 weeks) Antigen presentation by APC Occur in regional lymph nodes Priming of antigen specific CD4 cells

• Effector phase due subsequent exposure to the antigens (peaks 48-72 hrs)

Recruitment of antigen specific CD4 cells Influx of macrophages Secretion of pro-inflammatory cytokines

•Three variants of DTH:▫Contact Hypersensitivity▫Tuberculin-type Hypersensitivity▫Granulomatous Hypersensitivity

Contact hypersensitivity•aka contact dermatitis

Nickel watch Nickel pendant

Nickel ear ringRubber slippers

Rubber gloves Contact dermatitis due rubber gloves

Contact dermatitis• Occur at the point of contact with an allergen

(usually haptens)• Hapten: a small molecule that can not elicit an

immune response on its own• Haptens bind to carrier (tissue) protein to form

neo-antigen (immunogenic)• Uptake by Langerhans’ cells stimulation of

keratinocytes & pro-inflammatory cytokines • Present to T cells at regional lymph nodes• Recruitment of effector T cells and macrophages• Dermatitis (eczema)

Patch test

Tuberculin hypersensitivity•Seen following tuberculin skin test (TST)

or Mantoux test•Induced by soluble antigens from a

variety of organism•Originally developed by Koch in 1890•Current technique in use was described in

1912 by Charles Mantoux, a French physician

•Soluble antigens introduced intradermally•Characteristic skin-test reaction

(induration) that peak after 24 hours

•Skin induration is thickening of the skin due to migration of lymphocytes and macrophages into the dermis, the proliferation of cells in the dermis in response to cytokines, and the deposition of new extracellular matrix.

Mantoux test

•Positive reaction shows existence of antigen specific T cells (previous exposure)

Due pathogenic form of M. tuberculosis BCG vaccination

•Can be done for other infections as well

Granulomatous hypersensitivity•Due to intracellular pathogens that resist

macrophage killing•Chronic/ continuous T cell stimulation

leads to cytokine secretion (IL-3, IFN-γ & GM-CSF)

•Recruit & activate macrophages• Failure of eradicating intracellular

pathogens induces epithelioid cell transformation

•Epithelioid cells secretes TNF-α and induce cell fusion to form giant cells

Granuloma • Granuloma is composed

of a core of infected (and uninfected) macrophages, epithelioid cells, multi-nucleated giant cells (fusion of activated macrophages), along with peripheral accumulation of T lymphocytes, plasma cells, maybe a few neutrophils and fibroblasts with collagen; with or without central necrosis.

•Many chronic diseases manifest granulomatous hypersensitivity

•Most are due to infectious agents▫Tuberculosis (TB) M.tuberculosis▫Leprosy M.leprae▫Schistosomiosis worm schistosomas

•In some, no infectious agents has been established▫Sarcoidosis▫Crohn’s disease

Pulmonary tuberculosis

Leprosy • A chronic infection by

bacteria M.leprae and M.lepromatosis

• Initially infections are without symptoms and for 5 - 20 years. Symptoms that develop include granulomas of the nerves respiratory tract, skin, and eyes.

•This may result in a lack of ability to feel pain and thus loss of parts of extremities due to repeated injuries.

Reference•Immunology 7th edition, David Male et al.,

Mosby Elsevier, Canada. 2006.