Immuno Deficiency

Introduction
– Immunodeficiency: immune disorder when the IS
Fails to protect disease causing agents
– Not common
• Recurrent serious infection with frequent treatment
failures
 Types of immuno deficiency

Two broad categories of immunodeficiency

disorders are:
1. Primary immunodeficiency
2. Secondary immunodeficiency/Acquired
 Primary immunodeficiency
• Immunodeficiency resulting from
– Inherited genetic or developmental defects
– Also called congenital immunodeficiency
• Presents at birth but may not manifest until later in life
• Can be caused by defects in any gene involved in
immune development or function
– Innate or adaptive
– Humoral or cell mediated
 Primary…
• The degree and type of the immune defect is determined
by the nature of the component that fail
– Some are relatively minor: requiring little or no
treatment
– Others can be life threatening: Needs intervention
• Congenital immunodeficiency syndromes are under
diagnosed
• Basic knowledge of embryology of immunity is
essential to understand most congenital syndromes
 PRIMARY IMMUNODEFICIENCY
• Primary immunodeficiencies are generally the
result of genetic defects in the immune system cells

1) B-cell defects
2) T-cell defects

3) complement system defects

4) phagocytic system defects
 Primary defects of antibody production

• Of all of the primary immunodeficiency diseases, those

affecting antibody production are most frequent
 X- linked agammaglobulinemia
 Common variable immunodeficiency
 Selective IgA deficiency
 X- linked agammaglobulinemia
• Patients with X-linked agammaglobulinemia (XLA), or
Bruton agammaglobulinemia, have a profound defect in B-
lymphocyte development
• Absence of Bruton’s tyrosine kinase: defect in B-cell
development
• Resulting in severe hypogammaglobulinemia

– Absence of circulating B cells

– Small to absent tonsils

– No palpable lymph nodes
• Agammaglobulinemia is the severe of the antibody-
deficiency syndromes
• Significant decreases in all major classes of
immunoglobulins.
• An absence of circulating B cells .
 X-Linked
• The abnormal gene in XLA maps to q22 on the long
arm of the X chromosome and encodes the B-cell
protein tyrosine kinase Btk (Bruton tyrosine kinase)
 Clinical features
• Most boys afflicted with XLA remain well during the 1st 6–
9 month of life
– maternally transmitted IgG antibodies.
• Thereafter, they acquire infections with extracellular
pyrogenic organisms unless they are given prophylactic
antibiotics or immunoglobulin therapy
– Streptococcus pneumoniae and Haemophilus
influenzae
• Infections include sinusitis, otitis media, pneumonia,
or, less often, sepsis or meningitis. Infections with
Mycoplasma are also particularly problematic
• Viral infections are usually handled normally with
the exceptions of hepatitis viruses and enteroviruses
 Common variable immunodeficiency

• Hypogammaglobulinemia with phenotypically normal

B cells
• Later onset
• Equal sex distribution
• No identified molecular diagnosis
 Clinical features
• Normal or enlarged lymph nodes
• Splenomegaly in 25% of patients
• Sprue-like syndrome
• Follicular lymphoid hyperplasia of the intestine
• Thymoma
• Lymphoid interstitial pneumonia
• Non caseating sarcoid-like granulomas of the lungs,
spleen, skin, and liver also occur
 Selective IgA deficiency
• Most common of primary antibody deficiencies
– 1/500 to 1/1000 general population.
• Isolated or near absence of serum or secretary IgA
• Occasionally associated with ill health
• Basic defect is unknown
• Normal serum antibody responses.
• Normal cell mediated immunity
 Clinical features
• Infections occur predominantly in the respiratory,
gastrointestinal and urogenital tracts
• Bacterial agents responsible are the same as in other
antibody deficiency syndromes
• Intestinal giardiasis is common. Children with IgA
deficiency vaccinated intranasally with killed
poliovirus produce local IgM and IgG antibodies
 Treatment of B cell defects
• Antibiotics
• Intravenous immunoglobulins
• Stem cell transplant in XLA
Other primary antibody immune deficiencies

• IgG subclass deficiency

• Heavy and light chain deletions
• Hyper IgM syndrome
 Primary defects of cellular immunity
• In general, patients with defects in T-cell function
have infections or other clinical problems that are
more severe than in patients with antibody
deficiency disorders
• These individuals rarely survive beyond infancy or
childhood
 Cellular deficiencies include
• Combined immunodeficiency (CID)

• Severe combined immunodeficiency (SCID)

• Ataxia-Telangiectasia syndrome (AT)
• Wiskott-Aldrich syndrome (WAS)
• DiGeorge syndrome
 Thymic hypoplasia( DiGeorge syndrome)

• Dysmorphogenesis of 3rd and 4th pharyngeal

pouches
• Hypoplasia or aplasia of the thymus and
parathyroid glands
• The diagnosis is often first suggested by
hypocalcemic seizures during the neonatal period
 Clinical features
• Depends on the degree of thymic hypoplasia

• Partial vs complete thymic defect

• Mild infections to life threatening infections

• Can be associated with other congenital anomalies

like cardiac defects..

 Primary Combined Antibody and Cellular
Immunodeficiencies

• Patients with combined antibody and cellular defects

have severe, frequently opportunistic infections that
lead to death in infancy or childhood unless they are
provided hematopoietic stem cell transplantation early
in life
 Severe combined immunodeficiency(SCID)

• 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.
 clinical conditions

• All patients with SCID have very small thymuses (<1 g)

that usually fail to descend from the neck, contain no
thymocytes, and lack corticomedullary distinction or
Hassall corpuscles
• Infants with SCID have lymphopenia at birth
• Serum immunoglobulin concentrations are diminished
to absent
• No antibodies are formed after immunizations
 Clinical…
• Recurrent or persistent diarrhea
• pneumonia,
• otitis media
• sepsis
• cutaneous infections
• Persistent infections with opportunistic organisms
including Candida albicans, Pneumocystis carinii,
varicella-zoster virus
 Combined immunodeficiency (CID)
• CID is distinguished from SCID by the presence of
low but not absent T-cell function.
• Similar to SCID, CID is a syndrome of diverse genetic
causes.
• Patients with CID have recurrent or chronic
pulmonary infections, failure to thrive, oral or
cutaneous candidiasis, chronic diarrhea, recurrent
skin infections
 CID
• Neutropenia and eosinophilia are common
• Die later than SCID patients
• Serum immunoglobulins may be normal or elevated for
all classes, but selective IgA deficiency
• Marked elevation of IgE, and elevated IgD levels occur
in some cases
• Although antibody-forming capacity is impaired in most
patients, it is not absent
 Treatment of Combined defects
• Good supportive care including prevention and
treatment of infections is critical while patients await
more definitive therapy
• Immunoglobulins
• Transplant
 Deficiency of the complement system
• Complement deficiency: Absent or suboptimal
functioning of one of the complement system proteins
• The disorders can be divided into two categories:

1. Disorders of the proteins that act to inhibit the

complement system (such as C1-inhibitor) can lead to
an overactive response, causing conditions such as
– hereditary angioedema
– hemolytic-uremic syndrome
 Complement….
2. Disorders of the proteins that act to activate the
complement system (such as C3) can lead to an
underactive response, causing greater susceptibility
to infections
 SECONDARY IMMUNODEFICINCY
• Secondary immunodeficiency/acquired
immunodeficiency is the loss of immune function that
results from exposure to an external agent, often an
infection
• Much more common than the primary ones

• 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
• Systemic disorders • Surgery
– Ig hypercatabolism • Malignancies
– Excess loss of Ig • Infectious diseases
– Renal insufficiency – HIV, B cell and plasma cell
– Extensive burns malignancies
• Drug induced – Thymoma
– Cytotoxic – Non Hodgkin’s lymphoma
– Glucocorticoids – Congenital rubella
– Captopril – Congenital toxoplasmosis
– Carbamazepine – Epistein-Barr virus
– Phenytoin • Malnutrition
– Alcohol, – zinc
– Vitamins ( folic acid, vit A) 33
 Clue about Nature of immunodeficiency
• Repeated pyogenic infections (otitis media, pneumonia)
– Atrophied peripheral lymph nodes and tonsils
– B lymphocyte deficiency
• Severe mycotic infections, disease after live vaccine
– T lymphocyte deficiency

• Abscess formation (staph, serratia, aspergillus)

– Neutrophil deficiency
• Repeated Neisseria infection
– Complement deficiency
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 Agent induced immunodeficiency
• Cause is chemicals, biological agents

– Drugs for autoimmune diseases, steroids

– Post transplant – cyclosporine A

– Radiation therapy

• Higher risk of infection

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 Immunotherapy:
IMMUNOPROPHYLAXIS and
Vaccines
 Objectives

• Define Immunotherapy , prophylaxis

• What vaccine is
• The need for vaccine
• Vaccine types
• Principles of vaccination
• Features of effective vaccine
 Immunotherapy
• Infection prevention is desirable in patients who exhibit a
defect/s in host defense
• Immunotherapy: Category of therapies that use the
body’s immune system
• By immunosuppression or immunopotentiation of
immune system
• Fight cancer cells, allergies, autoimmune disease and
other diseases
 Immunotherapy…
• Immunotherapy drugs are designed to alert the immune
system about mutated cells so that it can locate and destroy
them
• Deferent methods used to improve host defense
– Prophylaxis
– Vaccine
– Antibodies
– Cytokines
 Prophylaxis
• Means of partially improving host defense through
prophylactic antibiotics
• Taking medicine to prevent rather than to treat a disease
or condition
• Used in those settings where patients are at increased risk
for a specific type of infection
For example:
 Taking pills to prevent malaria when you travel

 Using hormonal contraceptives to prevent pregnancy

 Taking pills to avoid pneumonia, if you are at risk

Immunization and Vaccines
 What is Vaccine?
• A biological preparation that improves immunity to
a particular disease
– Attenuated or killed microorganisms
– Proteins derived from pathogens
– Genetic material: DNA and RNA
• Administered for the prevention, treatment, or to
reduce effect of infectious diseases
 Immunization: Process of eliciting a long-lived state of
protective immunity against a disease-causing pathogen
• Vaccination: process of administrating a vaccine
 Aims of Immunisation

– A vaccine is not a cure, but prevents infection or slows

disease progression
– Teaches the body to recognize and defend itself against
pathogens that cause disease
• To protect those at highest risk

(selective immunisation strategy)

•To eradicate, eliminate or control disease

(mass immunisation strategy)

 Herd immunity?? Preventing spread of infection
 Control
• Reduction of disease incidence, prevalence, morbirity
and mortality
 Disease no longer considered as a significant
public health problem e.g. neo-natal tetanus
Elimination
 Disease has disappeared from one area but remains
elsewhere e.g. polio, measles
Eradication
 Infection (pathogen) has been removed worldwide
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e.g. smallpox
 When started?
The early vaccination trials were performed by Edward
Jenner (1978) and Louis Pasteur

Edward Jenner inoculating James Phipps with cow pox,

1796
 Vaccin…

• Since then, vaccines have been developed for many

diseases that were once major problems of mankind
• The incidence of diseases such as diphtheria, measles,
mumps, pertussis, rubella poliomyelitis, and tetanus
has declined dramatically due to vaccination
• Vaccination is proved to be a cost-effective weapon
for disease prevention
 Immunization procedures
• Two basic procedures by which organisms made
immune to infections are:
Passive vaccines
• Protection transferred ( usually by abs) from resistant
person or animal susceptible ones
• Temporary protection that wanes with time
Active vaccination
• Involves administration of antigens to a host so that it
respond by mounting immune response
• Usually, it provides permanent/long lasting immunity
 Types of Active vaccines
Whole organism Subunit vaccine Genetic Vaccine
vaccine

protein-based
Live attenuated toxoid polysaccharide
viral Recombinant -based DNA, RNA
bacterial protien pure
Conjugate
Inactivated Vaccines
viruses 48

bacteria
 Whole organism Vaccine
• Attenuated virus or bacteria are used as a vaccine
• Microbes lose their Pathogenicity but retain their
capacity for transient growth within an inoculated host
• The IR to a live attenuated vaccine is virtually identical
to that produced by a natural infection

• The immune system does not differentiate between an

infection with a weakened vaccine virus and an infection
with a wild virus
• Live attenuated vaccines produce immunity in most
recipients with one dose, except those administered
orally
 Methods of Attenuation

• Growing a pathogen under abnormal culture conditions

• E.g. BCG was render avirulent by culturing M.bovis on
bile salt saturated medium for 13 years
• Vaccine strain of anthrax made avirulent by growth in
50% serum agar in atm rich in CO2 so that it lose its
ability to form capsule

• Prolonged virus culture with the cells to which it is not

adapted. Virus adapted to lymphocytes…… with kidney.
• Passaging human pathogen through different hosts for
prolonged time. This method was used for virus
 Live attenuated vaccine advantages
• High immunogenicity- Replicate transient

-Low dose is required

• May not need adjuvants and can be applied by natural

route of infection

• Prolonged immune response & Induce memory

response

• No need of booster dose

• Capable of inducing cellular & humoral IR

 Current vaccines

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 Disadvantages of live vaccine

• Rarely revert to its virulent form and cause disease

Pathogens may mutate and regain their virulence. E.g.
Sabin polio vaccine =1 per 2.4 million
• May be associated with complications; E.g. measles
vaccine develop post-vaccine encephalitis or other
complications.
• Low stability (short shelf -life)
 Inactivated whole organism vaccine

• Inactivated vaccines are not alive and cannot replicate

• The entire dose of antigen is administered in the injection

• Cannot cause disease, even in an immunodeficient person

• Generally not as effective as live vaccines and require 3-5 doses

• Less interference from circulating antibody than live vaccines

• Immune response mostly humoral and diminish with time

 Methods of inactivation
• Killed organisms for vaccine are expected to remain as
antigenic as the live organism
• Inactivation of the pathogen by heat or by chemical
means were common approaches of vaccine
productions.
• Heat inactivation is generally unsatisfactory because it
causes extensive denaturation of proteins
• Common Chemicals used in synthesis of inactivated
vaccines are:
• Formaldehyde: cross-link proteins and nucleic acids,
and confers structural rigidity. The Salk polio vaccine is
produced by formaldehyde inactivation.
• Alkylating agents: such as ethyleneoxide,
ethyleneamine, β-propiolaceton cross-links nucleic acid
chains and leave surface protein unchanged.
 Current vaccines

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 Advantages

• Safe to use and can be given to immunodeficient and

pregnant individuals.

• Cheaper than live attenuated vaccine

• Storage not as critical as live vaccine

 Inactivated Exotoxin (toxoid)
• Bacterial pathogens, including those causing diphtheria
and tetanus, produce exotoxins…. Virulent factors.
• Diphtheria and tetanus vaccines can be made by:
• purifying the bacterial exotoxin, Inactivating the toxin
with formaldehyde to form a toxoid.
 Toxoid…
• Vaccination with the toxoid induces anti-toxoid
antibodies, which bind to the toxin and neutralizing
its effects.
• Toxoid production must be closely controlled to
achieve detoxification without excessive modification
of the epitope structure.
 Recombinant protein vaccines

• A gene encoding any

immunogenic protein can be
cloned and expressed in
bacterial, yeast, or
mammalian cells using
recombinant DNA technology
• The expressed antigens are
purified and used for vaccine
development
• Hepatitis B vaccine - vaccine
was developed by cloning the
gene for the major surface
antigen (HBsAg) and
expressing it in yeast cells
 Advantages

• Avoid the risks associated with live attenuated

vaccine
• Fairly stable
• Induce memory response
 Disadvantages
• Elicits humoral response predominantly
• Possibility of contamination
• Change on native conformation, so that antibodies
produced against the subunit may not recognize
the same protein on the pathogen surface
• Practical complexity
 Conjugate vaccines

• One way to involve TH cells directly in the response to a

polysaccharide antigen is to conjugate the antigen to
some sort of protein carrier.
• For example, the vaccine for Haemophilus influenzae
type b (Hib), consists of type b capsular polysaccharide
covalently linked to a protein carrier, tetanus toxoid.
• The polysaccharide-protein conjugate is:
– Considerably more immunogenic than the
polysaccharide alone
– Because it activates TH cells, it enables class
switching from IgM to IgG.
• Although this type of vaccine can induce memory B
cells, it cannot induce memory T cells specific for the
pathogen.
 Genetic Vaccines
• Latest vaccines and are still experimental
• Like recombinant vaccines, genes for the desired
antigens are located and cloned

• In the case of gene vaccines, however, the DNA/RNA is

introduced into the muscle of the animal being
vaccinated

• Some muscle cells (mysteriously) express the pathogen

DNA (they make transcribe and translate it so you get
the protein) and thereby stimulate the immune system
• Both humoral and cellular immunity have been induced
by DNA vaccines.
 How do gene vaccines work?
• Following in vivo transfection of host cells with plasmid
DNA:
– DNA is taken up by cells and subsequently enters the
nucleus, where mRNA of the respective antigen is
transcribed and shuttled back into the cytoplasm with
subsequent translation of the gene product.
• A finite amount of these newly synthesized proteins is
degraded within the cytoplasm by the proteasome and the
resulting peptides will be presented to CD8+ T cells in
association to MHC I molecules
• On the other hand, exogenous antigens secreted out from
transfected cells or released out upon death of these cells,
due to the transfection event, are taken up by APCs like
DCs.
• These cells process the internalized antigen and present the
resulting peptides to CD4+ T cells in association with MHC
II molecules.
• DCs can also be able to present exogenous antigens to CD8+
T cells on MHC I through cross priming.
 Advantages

• DNA is very stable

• A DNA sequence can be changed easily in the
laboratory.
• The inserted DNA does not replicate and encodes only
the proteins of interest.
• Induce both cellular and humoral response

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 Disadvantages
• Potential integration of DNA into host

• Induction of autoimmune responses

• Anti-DNA antibodies may be produced against

introduced DNA.

• Induction of immunologic tolerance

• The expression of the antigen in the host may lead to

specific non responsiveness to that antigen.
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 Principles of Vaccination

• Objective of immunization is to provide long‐lasting

immunologic protection against infectious agents
• To stimulate the immune response without causing actual
infection
• Primarily to prevent infection
• Strengthen an immune response that is inadequate,
particularly in chronic recurrent diseases
• Vaccination protects a recipient from pathogenic agents
by establishing an immunological resistant to infection71
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 Features of effective vaccine
Ideal vaccines should be:

• Immunogenic • Single dose

• Long lasting immunity • Affordable
• Safe • Accessible to all
• Stable in field conditions • Easy to store and
• Induce both humoral and administer
cellular immunity