Increased susceptibility to infection: Immunodeficiency

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Increased susceptibility to infection
Immunodeficiency

• Objectives
• By the end of the session you should be able to
• describe and list the way in which
  immunodeficiencies are classified
• list the primary immunodeficiencies and
  explain the mechanisms responsible for them
• describe and list the main factors leading to
  the development of secondary (acquired)
  immunodeficiencies
• list the main kinds of treatments for
  immunodeficiency

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Immunodeficiency

• An animal or human is said to have
  immunodeficiency if they show increased
  susceptibility to infectious organisms
• Immunodeficiency can be
• Primary or Congenital
• Secondary or acquired

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Immunodeficiency
Primary - components of the immune system are
absent eg. complement - genetic defect usually a
single gene Secondary - the result of damage to
other body systems (kidney, burns) or external
agents on the immune system ie immunosuppression
eg. irradiation, ccytotoxic drugs and microbes
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Types of Infections
Pathogens Opportunists
Types of infectious organisms give us a clue as
to what components of the immune system are
infected
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Antigenic mimicry
For example Viruses CMV b2 microglobulin (MHC
class I) hepatitis B myelin basic
protein vaccinia IL-1 receptor Bacteria Group
A strep human myocardium Klebsiella
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Complement deficiencies
a) hereditary angiedema - commonest C
deficiency b) early component deficiencies
that can lead to opsonin defects c) deficiencie
s in late components - membrane attack complex
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Complement deficiencies
Component deficient Disease caused/common
infections Regulatory components C1q
inhibitor Hereditary angiodema (continuous C
activation and consumption) Decay
accelerating factor Paroxymal nocturnal
hemoglobinuria DAF (CD55) (lysis of red blood
cells) Complement components C1, C2,C4 Immune
complex disease (unable to remove Ag-Ab
complexes), C2 deficiency associated with
SLE, C3 most serious repeated infections
with pyogenic bacteria MAC
complement Meningococcal infections eg.
Neisseria component deficiencies
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Classification of Immunodeficiencies
Primary (congenital) Inherent deficiencies
within the immune components -
genetic Secondary (acquired) The result of
external influences on the immune system -
microbes, drugs, failure of other body
systems etc.
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Defects in normal phagocytic function
b)
a)
a) PMNs unable to marginate - Leucocyte
adhesion deficiency (LAD) b) PMNs unable to
respond to chemotactic signals - Lazy Leukocyte
Syndrome c) Bacteria not opsonised - see C
deficiency d) Phagosomes (Ph) do not fuse with
lysosomes (Ly) - Chediak Higashi
Syndrome e) Lysosomes do not contain important
cytotoxic agents for killing - eg Oxygen free
radicals in Chronic granulomatous diseases
myeloperoxidase deficiency
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• B cell (antibody) deficiencies
• Pre B cells fail develop into mature B cells
  (Brutons disease
• Inherited B cell deficiencies
• Lack of T cell help
• Accessory function defects

T cell help
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• T cell deficiencies
• No thymus (thymic aplasia)
• Di George syndrome
• b) Accumulation of adenosine
• through defective adenosine deaminase (ADA) or
  guanosine through defective purine nucleoside
  phosphorylase (PNP) Also results in SCID
• Defective production of cytokines eg. IFNg and
  IL-12

Help for B cells
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X-linked immunodeficiencies
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Class switching is dependent on interaction
between CD40 on B cells and CD154 (CD40L) on T h
cells
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Single gene defects leading to immunodeficiency
Deficiency Gene affected Comments Leukocyte
adhesion CD18 part of LFA,MAC-1 deficiency Chr
onic granulomatous cytochrome B258 disease
(CGD) Complement deficiencies C2,C3,C4,C5-9 Seve
re combined Adenosine deaminase immunodeficiency
Purine nucleoside phosphorylase (SCID) gc
chain of cytokine receptors - (over 50
patients) IL-2,IL4,IL-7,IL-9,IL-15 Brutons
disease bruton tyrosine kinase (btk) different
mutations described in families Immunodefi
ciency with CD154 (CD40L) on T activated
T IgM CD40 on B no class switch
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Factors predisposing to secondary deficiency (1)
Factor Components affected Malnutrition Protein
-calorie malnutrition and lack of certain dietary
elements (eg. iron, zinc) world-wide the
major predisposing factors for secondary
deficiency Tumours Direct effect of tumours on
the immune system by release of
immunomodulatory molecules that are
immunosuppressive eg. IL10, TGFb Cytotoxic
drugs/ widely used for tumour therapy, but also
kills cells irradiation important to immune
response including stem cells, neutrophil
progenitors and rapidly dividing lymphocytes
in primary and secondary lymphoid
organs Aging Increased infections reduced
responses to vaccination decreased T and B
responses and their quality
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Factors predisposing to secondary deficiency (2)
Factor Components affected Trauma Increased
infections probably related to release of
immunosuppressive molecules such as
glucocorticoids Other diseases eg. Diabetes
this is often associated with infections but
the mechanisms are unknown Immunosuppression
Examples include malaria, measles virus but
especially by microbes HIV mechanisms involve
decreased T cell function
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Transient hypogammaglobulinaemia
Insufficient IgG passes across the placenta
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HIV
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CXCR4
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Mechanisms by which HIV results in immuno-
deficiency
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Additional molecules required for HIV infection
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Treatments for imunodeficiency

• Antibiotics
• Passive antibody (immmunoglobulins)
• Cellular engineering
• Stem cell therapy eg. Reticular dysgenesis
• SCID
• Chronic granulomatous disease
• (Problems - histocompatibility)
• Future - Gene therapy