DISORDERS OF IMMUNITY

Presenter Dr. Matingae

Facilitator: Dr. Mwendwa
 Learning objectives

 By the end of this lecture you should be able to:

 Describe the immune system evolution

 Understand how tolerance is classified

 Distinguish between anergy and hypersensitivity

 Compare congenital and acquired immune disorders

 Immunity

 The immune system is designed to protect the body

against injurious factors- external, internal
 Able to distinguish ‘self’ from ‘non-self’
 Innate; acquired ( cellular, humoral )
 Body mounts an immune response  destruction of
injurious factor
 Disorders of immunity

 Result from dysfunction or deficiencies in the immune

system
 The disorders include:
I. Hypersensitivity
II. Autoimmunity
III. Immunodeficiency
 Hypersensitivity

 Describes mechanisms that the body uses to combat

injurious agents but which result in a given disorder.
 The immune response results in host tissue injury
 Response is exaggerated or inappropriate
 Requires pre-sensitization
 Classified into 4 types by Coombs and Gell ( 1970)
 Classification criteria

 The classification into 4 types is based on the

following immune-mechanisms:
I. Antibody involved
II. Nature of the antigen
III. Type of cell involved
IV. Duration of the reaction
 Type I hypersensitivity

 Also called immediate hypersensitivity- mediates allegic

reactions
 Antibody mediated- IgE
 Antigen- allergens
 Needs sensitization
 Effector molecules- histamine ( early), bradykinin, 5-HT, slow
reacting substance P, LT
 Cells involved- mast cells ( early), N,Eo,Mo ( delayed phase)
 Response- vasodilatation, visceral smooth muscle contraction,
increased vascular permeability, mucus secretion
 May have a genetic component- atopy
 Manifestation

Manifests as allergic reactions

Localized- ag introduced locally
I. Asthma
II. Hay fever
III. Urticaria
IV. Allergic rhinitis, gastropathy

systemic
I. Anaphylaxis- ag exposed parenterally
Causes hypotension, broncospasm, angioedema,
Medical emergency
 Testing

 Serum IgE levels

 Skin prick test – itchy red lesion within 15- 20 min
 Mast cell tryptase
 Type II Hypersensitivity

 Antibody mediated cytotoxic hypersensitivity

 Mediated by IgG or IgMbind Ag on a given cell
 Ab-Ag complex:
I. Activates complement- classical pathwayMAC
II. Mobilize and activates N,Eo,Mo,killer cells-
phagocytosis
III. Antibody-dependent cell-mediated cytotoxicity
 Death of cell expressing Ag.
 Clinical examples

 Haemolytic disease of the newborn

 Transfusion reactions
 Myasthenia Gravis
 Glomerulonephritis- post streptococcal
 Allograft rejection- hyperacute
 Autoimmune hyperthyroidism
 Most autoimmune disorders
 Type III hypersensitivity

 Immune complex mediated

 Important response especially exotoxin removal
 Ab-ag complexes are formed and deposited in tissues
or vascular endothelium
 Deposited locally, systematically
 Normally phagocytized and destroyed, but if too
many or too small for phagocytosis lead to
pathology.
 Cont’d….

 Mechanism- complement activation- anaphylatoxins,

chemotaxis and phagocytosis by PMN,
 Tissue injury results
 Clinical examples

 Serum sickness- vasculitis due to exposure to serum

that has antitoxins ( ab to toxins)-venom,
diphtheria,tetanus
 Rheumatoid arthrits
 Post streptococcal glomerulonephritis
 SLE
 Arthus reaction
 Type iv/delayed
hypersensitivity

 Mediated by helper T cells( TH1)

 Exemplified in granuloma formation from TB
 APC presents Ag to the TH1 cells which become
activated with clonal expansion- 1 – 2/52
 Re-exposure  cytokines Macrophages
recruitment  phagocytosis – 48- 72 hrs
 Effective in killing IC microbes
 Cont’d…

 If the microbe persists, Mac fuse into giant

cellsgranuloma extensive tissue damage with
caseation, fibrosis and calcification.
 Other examples- contact dermatitis, chronic
transplant rejection,inflamatory bowel disease, RA,
tuberculin skin test.
 IMMUNEDEFICIENCY

 Deficiencies of aspects of the immune system leading

to compromised ability to defend body against
invasions
 Results in more opportunistic infections and
increased risk of cancers.
 Types
I. Primary( congenital)
II. Acquired( secondary)- more common
 immunodeficiency

 Antibody deficiency extracellular infections

 T- cell deficits leads to viral, fungal and or intracellular
infections- MOSTLY OPPORTUNISTIC
 Complement and phagocytic deficiency – pyogenic
infections.
 Acquired

 Leukemia
 Bone marrow disorders
 Infections- HIV infection
 Malnutrition
 Drugs- dmards, cytotoxic drugs, immunosuppressants
and modulators
 Chronic diseases/infections – SLE, DM
 Ageing
 congenital

 Hereditary- alone or as syndromes

 Autosomal recessive, x-linked
 types

 Based on the affected immune system component

Humoral immunodeficiency

 B cell defectsab deficiency

 Commonest of the primary IDs
 Susceptibility to bacterial infections- especially
encapsulated bacteria-stept, staph.
 Pyogenic and sinopulmonary infections
 Hypogammaglobulinemia- mild
 Agammaglobulinemia- severe to fatal
Humoral immunodeficiency

 Examples-
 Selective IgA deficiency
 CVID
 X-linked agammaglobulinemia of Bruton
 Common variable hypogammaglobulinemia
 Treatment is usually by Ig administration
 Selective IgA deficiency

 Most common primary ID in adults

 Reduced IgA levels, other IG are normal
 Mucosal infections- Gut, Conjuctiva and resp. tract.
 Mostly asymptomatic
 Inability of B cells to terminally differentiate into IgA
secreting plasma Cells.
Cellular immunodeficiency

 T cell defect- lack of cell mediated Immunity

 Increased viral, fungal, mycobacteria and other
opportunistic infections- Pjp
 Increased risk to immunization with live vaccines
 Also results in Ig deficiency since T cells are necessary
for proper function of B cells
 Most common- DiGeorge synd, ZAP 70 deficiency,
Chronic mucocutaneous candidiasis, wiskott- aldrich
syndrome
 DiGeorge syndrome

 Also called congenital thymic aplasia

 Profound T lymphocytopenia – impaired Tcell
maturation  impaired cell mediated immunity
 Mostly have normal B cells and humoral activity.
 Defective embryonic development of organs derived
from the 3rd and 4th pharyngeal arches- parathyroids,
thymus and cardiac outflow tract.
 Chromosome 22 deletions
Combined humoral-cellular ID

 B and T cell defects

 Form 20 % of IDs
 Examples-
 Severe Combined immunodeficiency
 Hyper IgE Synd
 Ataxia telengiectasia
 Severe combined
immunodeficiency

 Bubble boy disease- need a sterile space in order to

survive
 Affected by severe infections early in life.
 Genetic disorder due to poor development of
functional T and B lymphocytes.
 Most severe form of the primary IDs
 Fatal within 1-2 years in the absence of Bone Marrow
Transplant
 Phagocytic cell defects

 10-15% primary ID
 Defective microbicidal activity- hydrogen peroxide,
oxygen radicals,superoxide,
 Phagocytosis maybe normal in this cells,but the cells
cant kill the invading organisms
 Deficiency of NADP OXIDASE
 Defective adhesion molecules
 Phagocytic defects

 EXAMPLES-
 Chronic granulomatous disease( lack of NADPH oxidase
 impaired oxidative metabolism comrpomised
killing of phagocytosed pathogens )- recurrent
abcesses,granulomas
 Leukocyte adhesion deficiency – lack of B-2 integrin
 Chediak- higashi syndrome- cell unable to lyse
phagocytized bacteria- large phagosomes.
 treatment

 Avoid exposure to infectious agents

 Prophylaxis – antifungals, antibiotics
 Bone marrow transplants- may offer definitive cure
 Complement deficiency

 Rare
 Isolated deficiency of complement components or
inhibitors
 Hereditary or acquired
 Repeated infections- no opsonization
 The deficiencies result in defective opsonization,
phagocytosis, and lysis of pathogens
 defective clearance of antigen-antibody complexes.
 Complement disorders

 Most are autosomal recessive- exclude C1 inhibitor (

AD) and Properdin ( x linked)
 Lead to:
 recurrent infections( defective opsonization)
 autoimmune disorders – defective clearance of
immune complexes
 Complement deficieny

 Early classical pathway components-c1, c2,c4- usually

no severe infections but are predisposed to
autoimmune disorders
 Deficiency of C3 ( main opsonin) leads to frequent
and recurrent pyogenic infections and a high rate of
morbidity and mortality
 Late complement deficiencies- leads to lytic
deficiencies no MAC formed. Less morbidity and
mortality cf C3 deficiency.
 Immunity and ageing

 Immunity does decrease with advancing age.

 Mechanisms
I. Thymus reduces production of Naïve T cells
II. Reduced signal transduction
III. Reduced phagocytic and microbicidal activity of
Neotrophils
IV. Malnutrition
V. Chronic diseases
VI. drugs
 Autoimmunity

 Abnormal immune response to a normal body part

resulting in damage to the Host.
 Immunological reactivity to ‘self’
 Common end pathway is through the hypersensitivity
reactions- II,III, IV.
 Mechanisms

 Failed immune tolerance

 Release of sequestered antigens- from immunologically
priviledged sites( sympathetic ophthalmia)
 Molecular mimicry-rheumatic heart disease, M. gravis,
glomerulonephritis
 Failed immune tolerance mechanisms- escape from anergy
or defective apoptosis
 Bystander effects
 Alteration of normal host antigens- chemically, physically,
biologically
 Self tolerance

 Mechanisms by which T and B cells are prevented

from reacting to self
 T cell ‘schooling’ is more strict than for B cells.
 Central – T cells ( thymus), B cells( bone Marrow),
Negative selection( early clonal deletion)
 Self antigens are presented to naïve Lymphocytes
coupled with MHC proteins during preprocessing
 Those that show strong recognition of self antigens,
under go apoptosis.
 tolerance

 Genetic Defects in MHC proteins- cause antigen

presentation that results in low affinity engagement
with the naïve lymphocytes during preprocessing
 This are not selected reaction to self later(
tolerization )
 Injection of non-self antigen during preprocessing
leads to immune tolerance for this antigen.
 tolerance

 Peripheral tolerance: occurs in the secondary

lymphoid tissues
 Mechanisms:
 Lack of co-stimulatory molecules T cell activation
 Sequestration of antigens
 Apoptosis of T cells that enter immunologically
privileged sites
 Suppressor T – cells that suppress IR to self
 tolerance

1. Role of HLA
Genetic factors lead to altered HLA molecules
This weakly bind self antigens
Leading to non-selection of self reactive lymphocytes
2. Role of infections- polyclonal activation
- inappropriate MHC expression by
up regulating MHC II expression
 Anergy

 This is an inability of the immune system cells to

mount an effective immune response to an antigen-
unresponsiveness. Usually to self antigens.
 Mediates self tolerance
 One of the mechanisms of inducing tolerance-besides
clonal deletion and immunomodulation
 Mechanism

 T cell does not receive appropriate co- stimulation in

the presence of an antigen
 For full T cell stimulation- TCR along with co-
stimulatory receptors need activation.
 Calcium ions is released  calceneurin  activation
of NFAT( nuclear factor of activated Tcells which is a
transcriptional factor) inc IL-2 expression.
 Co- stimulation thro’ cd28 activates other
pathways of IC signaling including AP 1.
 anergy

 AP- 1 and NFAT forms a transcriptional complex  full

response,eg production of IL-2 and its receptor.
 In absence of co-stimulation only NFAT is formed. This
forms a complex with itself.
 This transcriptional factor induces anergy associated
genes in cell eg expression of ubiquitin ligase or
caspase 3
 Also expression of IL-2 and TNF is reduced
 Instead the cell produces anti-inflamatory agents - IL-
10
 anergy

 Anergy induced when-

 Antigen is poorly presented by the APC- no
costimulation
 Well presented Ag induces weak activation of the TCR
leading to activation of NFAT but not AP 1
Can be broken by strong stimulation by IL-2 0r by
TCR/costimulatory receptors
 Clinical significance

 Minimization of IR to transplanted tissues-

cyclosporine which weakens the immune response
selectively to transplanted tissues; without
weakening response to other antigens.
 Induce unresponsiveness of Immune system in auti-
immune ds- dm,ms,ra- by making activated T cells
unresponsive
 Tumour mx- prevent anergy in response to tumour
growth
Cell mediated autoimmunity

 Type IV hypersensitivity reaction

 T cells that are immunized against autologous
tissue injury in specific organs
 Due to diminished suppressor T cells or loss of clonal
anergy leading to auto reactivity
 Mechanism is seen in SLE
 Antibody mediated
autoimmunity

 Type II hypersensitivity reaction opsonozation,

complement activation, ADCC
 Antibodies are directed at autologous cell membrane
components. Complement activation and cell death
 examples
 Autoimmune hemolytic anemia
 Idiopathic thrombocytopenia
 Goodpasture syndrome
 Cont’d

 Anti-receptor antibodies- competitive agonists for cell

surface receptors
 Grave’s disease.
 Insulin resistance in type I DM- anti insulin receptor
antibodies
 Immune complex
autoimmunity

 Type III hypersensitivity reaction

 Antibodies bind to an antigen in serum.
 This are deposited in the BM of various organs
 Activation of compliment follows with attendant
inflammation and tissue injury
 SLE, Rheumatoid Arthritis, hemolytic anemia- drug
induced.
 Transplant immunology

 Allograft rejection
 Types-
 Host vs graft reaction( HVGR)
 Graft Vs Host Reaction ( GVHR)
 Host Vs Graft reaction

1. Hyperacute
 Within minutes
 Mediated by preformed cytotoxic T cells
 Complement activation, coagulation, microvascular
thrombosis with graft infarction
2. Accelerated rejection-
Within 4 days
Cellular and humoral mechanisms in a sensitized host
 Cont’d….

3. Acute rejection
Within 1 month
T cell mediated

4. Chronic rejection
Slow loss of function over months to years
 mechanisms

 Sensitization phase
 Host is exposed to the donor antigens with the
sensitization of T cells
 The cytotoxic T cells are activated
 Destruction Phase
 Cytotoxic t cells directly kill graft cells
 Lymphokines activate macrophages
 Graft Vs Host reaction

 Donor immunologically active cells attack host cells.

 Recipient may be immuno-compromised.
 When there is an antigen mismatch- allogenic grafts
 Bone marrow or stem cell transplant.
 Billingham criteria- immunocompetence of graft+ histi
incompatibility + immuno compromised host.
 Treatment options

 Induce immunosuppression- Azathioprine, kill T

lymphocytes by killing rapidly dividing cells
 Glucorcorticoids- prevent Cytotoxic T- cell
proliferation by inhibiting IL-2
 Inhibit formation of cytokines eg IL-2,- tacrolimus and
cyclosporine inhibit phosphorylation of NF-AT
 Induce anergy- inhibiting costimulatory necessary for
full T cell responses
 END.

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