Immunodeficiency

1

• Immunodeficiency
• Immunology of Pregnancy
• Immunity in the Elderly

2

• Lecture objectives are to understand
• How do microbial pathogens evade the immune
  system?
• Genetic disorders that cause immunodeficiency
• How does AIDS virus evade the immune system and
  cause immuodeficiency?
• Why does the immune system become weaker as we
  get older?
• Why are fetuses not rejected in pregnant mothers
  despite their MHC differences?

3

• Why do we fail to mount effective immune response
  to pathogens?
• 1. Congenital immunodeficiency
• (defective immune cells or molecules of the
  immune system)
• 2. Acquired immunodeficiency by Human
  Immunodeficiency Virus
• 3. Pathogens can evade the immune system
• (e.g. multiple serotypes, mutations, gene
  conversion, hiding in dormant state, blocking
  immune response, and superantigens)

4
24. Immunodeficiency Diseases
CORE

• General signs and symptoms of immunodeficiency
  diseases
• Usually patients suffer from chronic infections
  of opportunistic pathogens
• High incidence of cancer

5

• You are immune-deficient if defective in any of
  the following components of the immune system
• Signaling molecules in TCR activation
• Key transcriptional factors of immune cells
• Molecules and organs for lymphocyte development
• Antigen presentation
• Phagocyte function
• Cytokines and co-stimulation molecules
• Immune cell migration and adhesion
• Complement
• DNA recombination and metabolism

6
CORE

• b. Laboratory tests to assess immune function
• (1) T cell Enumeration (flow cytometry),
  functional assays (mitogen response, MLR, DTH
  skin tests)
• (2) B cell Enumeration, circulating antibody
  levels
• (3) Macrophage Enumeration, functional assays
  (nitroblue tetrazolium)
• (4) Complement Direct measurement of complement
  components, complement hemolysis assay

7
CORE

• Primary B cell immunodeficiencies (symptoms,
  description of defects, current therapy)
• (1) X-linked Agammaglobulinemia (Bruton's
  syndrome) btk deficiency
• (2) Common Variable Immunodeficiency (acquired
  hypogammaglobulinemia)
• (3) Selective IgA deficiency (most common
  immunodeficiency disorder)
• (4) Other (minor)
• (a) Transient hypogammaglobulinemia of infancy
• (b) Selective deficiency of IgG subclasses
• (c) Immunodeficiency with hyper IgM

8
CORE

• Primary T cell immunodeficiencies (symptoms,
  description of defect, current therapy)
• (1) Congenital thymic aplasia (DiGeorge's
  Syndrome or Third and Fourth Pharyngeal Arch
  Syndrome)

9
CORE

• e. Combined B and T cell immunodeficiencies
  (symptoms, description of defect, current
  therapy)
• Severe Combined Immunodeficiency (SCID a group
  of genetically determined diseases)
• X-Linked combined immunodeficiency (accounts for
  50-60 of all SCID defect in cytokine receptors)
• Adenosine deaminase deficiency (an autosomal
  recessive SCID accounts for 20 of all SCID)
• (c) Other mechanisms of SCIDs Purine nucleoside
  phosphorylase deficiency, TCR immunodeficiency,
  MHC class I or II deficiency (Bare Lymphocyte
  Syndrome), Defective IL-2 production

10
(No Transcript)
11
(No Transcript)
12
Figure 9-7 part 1 of 3
Inherited immunodeficiencies
Bubble boy
SCID
SCID
BLS
SCID
13
Caused by deficiency in common gamma chain (?c)
The Cytokine receptor common gamma chain (?c)
(or CD132) is a cytokine receptor sub-unit that
is common to the receptor complexes for at least
six different interleukin receptors IL-2, IL-4,
IL-7, IL-9, IL-15 and interleukin-21 receptor.
14
Figure 9-7 part 2 of 3
Inherited immunodeficiencies
Most common
15
Figure 9-8
X-linked agammaglobulinemia Mutation in the btk
gene Bruton's agammaglobulinemia tyrosine kinase
(btk). Failure in B cell development Males
are more affected
16
Figure 9-7 part 3 of 3
Other inherited immunodeficiencies
17
CORE

• f. Primary phagocyte deficiencies (symptoms,
  description of defect, current therapy)
• (1) Neutropenia
• (2) Chronic Granulomatous Disease
• (3) Leukocyte Adhesion Deficiency

18
Figure 9-10
Defects in phagocytic cells persistent bacterial
infections
19
CORE

• Primary complement deficiencies (symptoms,
  description of defect, current therapy)
• (1) Deficiency of Complement Components
• (a) Classic pathway C1, C4, C2, C3
• (b) Alternative pathway Factor D, Properdin
• (c) MAC C5, C6, C7, C8, C9
• (e) Regulator proteins Factors H, I, C1
  inhibitor
• Hereditary Angioedema (C1INH deficiency)

20
Deficiencies in the pathways of complement
activation
Clearance of immune (Ab-Ag) complex
Opsonin
Membrane attack
Enhances alternative path
Supplies C3
Prevent host cell destruction
21
Bone marrow transplantation is used to correct
genetic defects of the immune system
High degree of HLA matching between patients and
donors are critical

• To prevent alloreactions causing GVHD
  (graft-vs-host disease) and graft rejection
• For effective presentation of antigen to
  donor-derived T cells

22
CORE

• Secondary immunodeficiencies
• Drug or radiation-induced (steroids, other
  cytotoxic drugs)
• AIDS (HIV target cells and immune dysfunction
  see Virology for other aspects of the viral
  infection)
• Nutritional deficiency (reduced protein, calorie,
  biotin, B12, Iron, Vit. A, Zinc thymic atrophy
  pathologic result)
• Autoimmune Disease (?, frequent inflammatory
  diseases are found in immunodeficient patients)
• (5) Other (postviral, chronic infection,
  neoplastic diseases)

23
Acquired Immunodeficiency can be caused by
24
Figure 9-13
Human Immunodeficiency Virus
25
Figure 9-14
26
Progression of AIDS

• Infection
• viremia (increase of the virus load in blood)
• immune response to HIV generation of Tc cells
  and antibody to HIV (seroconversion)
• temporary reduction of virus-infected CD4 T cells
  (due to HIV-induced apoptosis and T cell attack)
• partial recovery of CD4 T cell number
• gradual decrease of CD4 T cell number over 2-15
  years (clinical latency is a period of active
  infection and CD4 T cell renewal)
• AIDS (CD4 T cell count lt 200)

27
Acquired Immune deficiency syndrome

• HIV infection through the host CD4 molecule and
  chemokine receptors (CCR5 or CXCR4)
• T cell activation is required for viral
  replication
• Initial viremia and CD4 T cell number decrease
  (asymptomatic or mild flu-like)
• Anti-HIV response and CD4 T cell number recovery
• Long clinical latency (2- 15 yrs) a period of
  active viral infection and CD4 T cell renewal
  gradual CD4 T cell number decrease
• Immunodeficiency starts when the CD4 count is
  below 500 ? Opportunistic infection
• Death due to secondary infection

28
HIV receptor and coreceptors

• HIV receptor CD4
• Co-receptors chemokine receptors CCR5 and CXCR4
• Macrophage-tropic virus infects macrophages, DCs
  and some T cells through CCR5 (early stage virus)
• Lymphocyte or T-tropic HIV infects T cells
  through CXCR4 (late stage virus).
• Switch from M-tropic to T-tropic occurs in 50 of
  cases.
• HIV replication requires T cell activation (NF-Kb
  for viral RNA transcription)

29
Figure 9-15
The life cycle of Human Immunodeficiency Virus
30
Gradual loss of CD4 T cells after infection

• There are long-term non-progressors some remain
  seronegative
• Some people have mutant CCR5 thus can be
  resistant to HIV

31
Figure 9-20
Combination drugs are effective in reducing HIV
in patients
However this is not complete elimination
32
Figure 9-22
Opportunistic infections and malignancies kill
HIV patients
33
Immune cells involved in anti-HIV response
Adaptive Immunity
Innate Immunity
NK
DC
CD4
B
CD8
34
HIV why is it formidable?

• High mutability and slow progression
• Changes in viral antigens (immune targets)
• and enzymes (drug targets)
• Generation of viral variants
• Difficult to make vaccines
• High rates of vertical and lateral transmissions
• Targets CD4 T cells
• One HIV drug is effective transiently.
• Combination therapy using multiple drugs are more
  effective.

35
HIV evades host immune response by rapid mutation

• HIV and other retroviruses have error-prone
  reverse transcriptases, generating mutant variant
  viruses or quasi-species
• Selection of mutant viruses that have lost the
  epitope recognized by the host immune system
• Sometimes, homologous peptides of variant viruses
  interfere the presentation of the original
  peptides
• Such diversity greatly complicates vaccine
  development and limits the effectiveness of
  anti-viral drugs

36
Figure 9-1
Genetic variations within some species of
pathogens prevent effective long-term immunity
90 serotypes of Streptococcus pneumonia
37
Mutation and recombination allow influenza virus
to escape from immunity RNA virus has genome of
8 RNA molecules
Ag Neuraminidase and Hemagglutinin
Mutation leads to antigen drift mild and limited
epidemics
Recombination or swapping RNAs leads to antigen
shift severe pandemics, every 10-50 years
38
Unicellular protozoa that are parasites of
insects, plants, birds, bats, fish, amphibians
and mammals.
Trypanosomes undergo gene conversion to change
their surface antigens African trypanosomes
causes sleeping sickness, transmitted through
insect bites, and have 1000 copies of inactive
Variable Surface glycoprotein genes. Chronic
cycle of antibody production and antigen
clearance leads to a heavy deposition of immune
complexes, inflammation, neurological damages and
finally coma.
Another example is the pilin change by Neisseria
gonorrheae Salmonella tryphimurium alternates
expression of two flagellins
39
Herpes virus persists in human hosts by hiding
from the immune response in a dormant
state Herpes simplex virus causes cold sores,
first infect epithelial cells and then spreads to
sensory neurons. Viruses persist in a latent
state in the sensory neurons. Various stresses
reactivate the virus. Reactivated viruses infect
epithelial cells. Neuron is a favored place to
hide because it expresses low levels of MHC class
I molecules.
Other examples are the herpes virus
varicella-zoster causing shingles hides in
ganglia and Epstein-Barr virus causing
mononucleosis hides in B cells.
40
(No Transcript)
41
Figure 9-5 part 1 of 3
Mechanisms of viruses to subvert the immune system
42
Figure 9-5 part 2 of 3
Mechanisms of viruses to subvert the immune system
43
Figure 9-5 part 3 of 3
Mechanisms of viruses to subvert the immune system
44
Bacterial pathogens subvert the immune system

• M. tuberculosis prevents fusion of phagosomes
  with lysosomes
• Listeria monocytgenes escapes phagosomes
• Treponema pallidum coats itself with human
  proteins
• Staphylococci produces superantigens (SEB and
  TSST-1)
• Mycobacterium leprae induces Th2 response to
  evade Th1 CMI response

45
Figure 9-6
Superantigens induce polyclonal T cell
activation, inhibiting antigen-specific immunity
46
26. Immunity in the Elderly
CORE

• a. Effects of aging on the immune system thymic
  atrophy

47
25. Immunology of Pregnancy
CORE

• Mucosal immunity of the female genital tract (IgA
  secretion)
• Trophoblasts and immune responses
• Trophoblasts dont express MHC I and II (reduced
  immunogenicity of fetal cells)
• Active immune suppression by secretion of
  immunosuppressive factors such as
  a-fetoprotein,IL-10 and TGF-ß
• Inhibition by T-regulatory/suppressor cells

48
In pregnancy, the endometrium represents the
hosting surface for invading semi-allogeneic
cells (trophoblasts). The immunological
mechanism must provide a balanced environment
whereby the conceptus is nurtured by the mother
and yet prevented from excessive invasion.
Decidual natural killer cells play a role in
the implantation and early invasion of the
trophoblast. Regulatory T cells in suppression
of immune responses against fetus (?)
49
Immunological factors leading to pregnancy failure
Stages of normal pregnancy Gamete
Development Fertilization Embryo
Cleavage Trophoblast formation Implantation Fet
al Development Parturition
Anti-sperm Ab Defective adhesion
molecules Anti-phospholipid Ab Aberrant HLA
expression NK cell attack (inhibited by
HLA-G) Too much Th1 cytokine? T cell
attack Lack of suppressor T cells
50
1. RhD- mother can reject RhD fetus at second
pregnancy.
Hemolytic disease of the fetus and newborn
Anti-RhD (IgG) antibodies can cross placenta.
Administration of anti-RhD antibodies (Rhesus
prophylaxis) either during pregnancy or
immediately after delivery can prevent it.
2. Why does not a blood type O mother reject A
type fetus?
Anti-RhA or B (IgM) antibodies can not cross
placenta.
3. An RhD-/type O mother carrying an RhD/type A,
B, or AB fetus is resistant to sensitization to
the RhD antigen .
No hemolytic disease in this case. Anti-A/B
clears fetal cells in the mom.
51

• Summary Why do we fail to mount effective immune
  response to pathogens?
• Pathogens have been evolved to evade the immune
  system
• (e.g. multiple serotypes, mutations, gene
  conversion, hiding in dormant state, blocking
  immune response, superantigens)
• Congenital immunodeficiency
• (defective immune cells or molecules of the
  immune system)
• Acquired immunodeficiency
• (AIDS/Human immunodeficiency virus)

52
CORE

• Immunosuppressive drugs (mechanisms of action and
  examples of their uses)
• (1) Cycle-nonspecific (radiation,
  corticosteroids, nonsteroidal anti-inflammatory
  agents, cyclosporin)
• Cycle-specific (cyclophosphamide, chlorambucil,
  azathioprine, methotrexate) nucleotide analogs
• See the Transplantation Immunology Lecture

53
c. Pathologically induced immunosuppression
CORE

• Immunodeficient diseases
• e.g. AIDS
• Disease-induced anergy
• Inability to activate T cells in response to
  pathogens.
• Susceptible to super-infection by different
  pathogens.
• Evasion of immune responses by pathogens
• e.g. some pathogens induce regulatory T cells to
  suppress the responses.

See the Immunodeficiency Lecture