Undesirable and altered

immunity
 Introduction
Immune Disorder
• An immune disorder is a dysfunction of the immune system

• Immune dysfunction occurs as a result of improper regulation that

allows the immune system to

• Either attack something it shouldn’t or

• Fail to attack something it should

• Immune disorder cause abnormally low activity or over
activity of the immune system

 There are three types of immunological disorders

1. Hypersensitivity

2. Autoimmune disease

3. Immunodeficiency
 1. Hypersensitivity

• Effector molecules of IS induce a localized inflammatory response

that eliminates antigen without extensively damaging the host’s
tissue.
• Under certain circumstances, however, this inflammatory response
can have deleterious effects, resulting in significant tissue damage
or even death.
• These result from inappropriate and overly active immune
responses to common innocuous env’t Ag, such as pollen,food,
animal dander etc.. termed hypersensitivity or allergy.
Based on mechanics involved and time taken for the reactions HSR

reactions are four Types :

• Type I (Anaphylactic) Reactions
• Type II (Cytotoxic) Reactions
• Type III (Immune Complex) Reactions
• Type IV (Cell-Mediated) Reactions.
• Three types occur within the humoral branch and are mediated by
antibody.
• A fourth type depends on reactions within the cell-mediated branch
 IgE-Mediated (Type I) Hypersensitivity/
anaphylactic reaction

• It is also known as immediate hypersensitivity

• The reaction takes 15-30 minutes from the time of exposure to the
antigen.

• reaction is induced by certain types of antigens referred to as

allergens, and has all the hallmarks of a normal humoral response.

• Antibody class produced is different than the normal 1° response

(IgE)
• The primary cellular component in this hypersensitivity is mast cell
or basophil

• IgE produced by plasma cells is rapidly taken up by FcεRI on tissue

mast cells and circulating basophils
 Mechanism type I HSR
• Allergen is recognized by naïve B cell

• B cell stimulated by T helper cell through IL4

• IgE specific for allergen binds to mast cells/basophils 

sensitized

• 2nd exposure to allergen Cross linkage of IgE on mast cells

• triggers degranulation of mast cells/basophils

IgE-Mediated (Type I) Hypersensitivity

6.
4.
3.

2. 5.
Common allergens associated with type I hypersensitivity

Source: Kuby Immunology 2007 5th ed

Three classes of mediators derived from mast cells:
1.Preformed mediators stored in granules

Histamine – major portion of granules, decarboxylation of

histidine

2. Newly sensitized mediators:

Leukotrienes and prostaglandins produced from Phospho lipid

breakdown, promote further contraction of smooth muscles

3. Cytokines (IL-4,5,6, TNF-α) released from Mast/Baso, -attract

neutrophils, eosinophils, IgE production from B cells, TNF may
contribute to systemic anaphylaxis.
These mediators cause:

• smooth muscle contraction,

• mucous secretion
• bronchial spasm
• vasodilatation,
• vascular permeability
• edema
 Type I Responses may be Systemic or Localized

Systemic response (Anaphylaxis):

• occurs in minutes;
• symptoms include: difficulty in respiration, BP drop, smooth
muscle contraction, massive edema.
• A wide range of Ag have been shown to trigger this reaction in
susceptible humans, including
venom from bee, . See food and nuts
wasp, hornet, and ant stings;
drugs, such as penicillin, insulin, and antitoxins
• If not treated quickly, these reactions can be fatal.

• Epinephrine is the drug of choice for systemic anaphylactic

reactions.

• counteracts the effects of mediators such as histamine

and the leukotrienes

• increases cAMP levels in the mast cell, thereby blocking

further degranulation.
Localized response (Atopy):
• limited to target tissue/organ often at epithelial surfaces
• The tendency to manifest localized anaphylactic reactions is
inherited and is called atopy.
• Atopic allergies include:

• Allergic rhinitis (hay fever)

• Asthma

• Atopic dermatitis (eczema)

• Food allergies
 Type II (Cytotoxic) Reactions

• Mediated, primarily, by antibodies of IgM or IgG class and

complement

• Affect a variety of organs and tissue and the reaction time is minutes
to hours.

• Directed against cell surface or tissue antigen

• The Ag are normally endogenous, although exogenous chemicals

(haptens) that can attach to cell membranes can also lead to type II
HSR.
 Mechanism of Cytolysis

Cell lysis results due to :

1) Complement fixation to antigen antibody complex on cell surface

• The activated complement will lead to cell lysis

2) Phagocytosis is enhanced by the antibody (opsinin) bound to cell

antigen leading to opsonization of the target cell
 Mechanism….
3) Antibody depended cellular cytotoxicity (ADCC):
- Antibody coated cells

e.g. tumor cells, graft cells or infected cells can be killed by cells
possess Fc receptors

- Cells most active in ADCC are:

NK, macrophages, neutrophils and eosinophils

• Examples of type II hypersensitive reactions

1. Transfusion Reactions

2. Hemolytic Disease of the Newborn

3. Drug-Induced Hemolytic Anemia

4. Autoimmune diseases
 Transfusion Reactions
• Cytotoxic hypersensitivity reactions can bring about the
destruction of some foreign blood cells.

• Anti-A and Anti-B in circulation will destroy erythrocytes from

other individuals.

• The body will destroy any incompatible red blood cells.

• Consequences of incompatible blood transfusion is potentially

life-threatening.

• Prevented by cross-matching blood.

Haemolytic Disease of the Newborn (HDN)
Drug-Induced Reactions: Adherence to Blood
Components

blood cell adsorbed drug

or antigen drug metabolite antibody to drug

complement

lysis
Immune Complex (Type III) Hypersensitivity

IC mediated Hypersensitivity
 When Ag combines with Ab in the body, an immune
complex is formed which normally culminates in the
elimination of the antigen.
 Immune complexes are removed by reticuloendoth.
syst.
 Some immune complexes escape phagocytosis
 Mechanism Of Tissue Injury
Immune complexes trigger inflammatory processes:

1) Immune complexes activate the complement

release anaphylatoxins C3a, C5a

stimulate
histamine degranulation of basophiles and mast cells
2. Neutrophils are attracted to the site by immune complexes
and release lysosomal enzymes which damage tissues and
intensify the inflammatory Process .
 Clinical conditions of Type III
Hypersensitivity
Diseases produced by immune complexes are those in which antigens
persists without being eliminated as:

a- Repeated exposure to extrinsic antigen

b- injection of large amounts of antigens

c- Persistent infections

d- Autoimmunity to self components

Clinical Conditions…..

1- Arthus Reaction

2- Serum Sickness

3-Post-streptococcal glomerulonephritis

4- Hypersensitive pneumonitis (farmer lung)

 Type IV (Cell-Mediated) Reactions
• Cell Mediated hypersensitivity reaction (TH1mostly,CD8 cells
occassionaly)

• DTH response does cause extensive tissue damage

• In many cases the response also plays an important role in defense

against intracellular pathogens and contact antigens
•The hallmarks of a type IV reaction are the delay in time required
for the reaction to develop and the recruitment of MФ as opposed to
neutrophils, as found in a type III reaction

•MФ are the major component of the infiltrate that surrounds the
site of inflammation.
 Examples of Microbial-Induced DTH
• Viruses (destructive skin rashes)

• Smallpox, measles, herpes simplex

• Fungi

• Candidiasis, dematomycosis, coccidioidomycosis,

histoplasmosis

• Parasites

• Leishmaniasis, schistosomiasis
 Phases of the DTH Response
Sensitization phase
• DTH response begins with an initial sensitization phase of 1–2
weeks after primary contact with an antigen

• During this period, TH cells are activated and clonally

expanded
Efector phase
• In the effector phase, TH1 cells secrete a variety of cytokines
that recruit and activate MФ and other nonspecific
inflammatory cells

• The delayed onset of this response reflects the time required for
the cytokines to induce localized influxes of macrophages and
their activation

• DTH response is important in host defense against parasites

and bacteria that live within cells, where circulating antibodies
cannot reach them
• a prolonged DTH response can itself become destructive to the host
as theintense inflammatory response develops into a visible
granulomatous reaction.
• A granuloma develops when continuous activation of Ms induces
the Ms to adhere closely to one another
• the response can damage blood vessels and lead to extensive tissue
necrosis.
E,g. response to Mycobacterium tuberculosis illustrates the double-
edged nature of the DTH response.
A prolonged DTH response can lead to formation of a granuloma, a
nodule-like mass. Lytic enzymes released from activated Ms in a
granuloma can cause extensive tissue damage.
 2.Autoimmune Disease

• This could be caused by a sudden inability of IS to distinguish between

self and non self or by a misinterpretation of a self-component as
dangerous.

• The recognition of self antigen by autoreactive lymphocytes( B/T)

results activation ,proliferation and differentiation of these cells to
effector cells and tissue injury

• The symptoms of autoimmunity differ, depending on which tissues or

organs are under attack
• Tolerance to self is acquired by:
1. CENTRAL TOLERANCE:- through Negative
selection /clonal deletion or receptor editing of
developing lymphocytes.
2. PHERIOHERAL TOLERANCE: Responsible
for tissue specific self Ags that are not abundant
in the thymus.
• Anergy (functional inactivation) Ag recognition
without adequate costimulation.
• Regulatory T cells inhibit immune responses in
part by producing immunosuppressive
cytokines.
How self tolerance fail and autoreactive lymphocytes
activated

• When there is a breach in central and peripheral tolerance.

• genetic factor (HLA alleles)- Alter the selection process

• Environmental :not clearly known

• Infection -bystander activation.(increase co stimulation

• Molecular mimicry- Some microbial antigens may cross-react

with self antigens
Examples of autoimmune
disease
hyperthyroidism, and the enlargement of the thyroid gland visible as goiter
 3.Immunodeficiency
• When the system fails to protect the host from disease
causing agents, the result is immunodeficiency.

• the immune system can be subject to failures of some or all

of its parts.
• Two broad categories of immunodeficiency disorders are:
1. primary immunodeficiency.
2. Secondary immunodeficiency
 1. primary immunodeficiency
• Primary immune deficiencies are inherited genetic defects of the
immune system ( also called congenital immunodeficiency).

• In such a condition, the defect is present at birth, frequently

manifested early in infancy and childhood.

• More than 120 different congenital forms of immunodeficiency have

been reported.

• including defects in lymphoid cells, phagocytic cells, and

complement proteins.
• The types of infection or symptoms can give important clues to the
specific immunodeficiency present.

• In general, defects in humoral immunity (antibody production)

result in extracellular bacterial infections, particularly of the upper
and lower respiratory tract.

• Defects in T-cell mediated immunity result in recurrent infections

with Intracellular pathogens such as viruses, fungi, and intracellular
bacteria
• Of all of the primary immunodeficiency diseases, those
affecting antibody production are most frequent.

• Basic defect is unknown

X- linked agammaglobulinemia
A mutation occurs at the Bruton's tyrosine kinase (Btk) gene
• that leads to a severe block in B cell development and a
reduced immunoglobulin production in the serum.

• have a profound defect in B-lymphocyte development resulting in

severe hypogammaglobulinemia, an absence of circulating B
cells, small to absent tonsils, and no palpable lymph nodes.
 Severe combined immunodeficiency(SCID)(rare )

• The syndromes of SCID are caused by diverse genetic

mutations

• that lead to absence of all adaptive immune function and, in

some, a lack of natural killer (NK) cells. Patients with this
group of disorders have the most severe immunodeficiency.
2. Secondary Immunodeficy
• Secondary immunodeficiency, also known as acquired
immunodeficiency, is the loss of immune function that
results from exposure to an external agent, often an
infection.

• Although several external factors can affect immune

function, by far the most well-known secondary
immunodeficiency is acquired immunodeficiency syndrome
(AIDS).
 Causes of secondary immunodeficiency

• Malnutrition
• Renal insufficiency
• Drugs
• Infection with cells of the immune system
Quiz
 Discuss innate and adaptive immunity
 Explain the primary or secondary lymphoid organs of immune
system
 Describe role of macrophages, natural killer cells, cytotoxic,
helper, B lymphocytes or plasma cells.