Download Immune deficiency syndromes

Immune deficiency
syndromes
Keri C. Smith
May 28, 2009
Immune deficiencies
 Primary

Hereditary or acquired
• Can be categorized based on clinical presentation




Cell mediated (T cell)
Antibody mediated (B cell)
Nonspecific (phagocytes, NK cells)
Complement activation
 Secondary

Immune deficiency is the result of another
disease
Major clinical manifestations of
immune disorders
Disorder
Associated Disease
Deficiency
B cell deficiency – deficiency in Ab
mediated immunity
Recurrent bacterial disease (otitis
media, recurrent pneumonia
T Lymphocyte deficiency – deficiency in
cell mediated immunity
Increased susceptibility to viral,
fungal,protozoal infection
T and B lymphocyte deficiency –
combined deficiency of Ab- and cellmediated immunity
Acute and chronic infections with viral,
bacterial, fungal, and protozoal
organisms
Phagocytic cell deficiency
Systemic infections with bacteria of
usually low virulence, infections with
pyogenic bacteria, impaired pus
formation and would healing
NK cell deficiency
Viral infections, associated with several
T cell disorders and X-linked
lymphoproliferative syndromes
Complement component deficiency
Bacterial infections;autommunity
Severe Combined
Immunodeficiency Disease (SCID)
 Life
threatening infections soon after birth
 Wasting, Failure to thrive
 Lack of Thymic shadow
 Lack of CD3+, CD4+, CD8+ and
lymphocyte response to antigens
“The Boy in the Bubble”
Primary immunodeficiencies
 Severe
Combined Immunodeficiency
Disease

T-B+
• X-linked SCID (40-50% of cases)

Lack g chain for common cytokine receptor
• Autosomal recessive SCID

Mutation in gene that encodes JAK3 tyrosine kinase
X linked and autosomal recessive
Primary immunodeficiency

Severe Combined Immunodeficiency Disease

T-B• Adenosine deaminase deficiency (20% of cases)

Missing housekeeping enzyme in purine salvage pathway,
autosomal recessive, buildup of toxic wastes affects B and T
cells
• Purine nucleoside phosphorylase deficiency

Purine salvage pathway, toxic wastes affect neurologic system
and T cells (these patients have autoimmunity?!)
• Recombinase deficiency

RAG 1 and 2 required for the rearrangement of Ig genes and
TCR. Cells are stuck in pre-B and pre-T stages. NK cell
function OK
Primary Immunodeficiency
 Severe
Combined Immunodeficiency
Disease

T+B• Omenn syndrome


“leaky” SCID with partial RAG activity. Th2 imbalance
and a tendency towards hyper IgE syndrome
T+B+
• Bare lymphocyte syndrome

Failure to express HLA molecules
• ZAP-70 mutation

Unable to signal through TCR
Failure to stimulate T cells
Multisystem disorders

Wiskott-Aldrich Syndrome





X linked mutation in gene encoding protein that interacts with
cytoskeleton
Bleeding, recurrent bacterial infections, allergic reactions
Abnormal B and T cells, low T cell count
Can be treated with antibiotics, antivirals, bone marrow
transplant
Ataxia Telangiectasia



Mutation in ATM gene
Manifests as staggering gait with abnormal vascular dilation
Increased susceptibility to infection, lymphopenia, depressed Ig
and T cell response
Treatment for SCID
 Bone
marrow/ placental stem cell
transplant
 IvIg if necessary
 Supportive care
 Gene therapy, if possible
 Avoid live viral vaccines!
 CMV-/irradiated/low WBC blood
transfusions
Future research directions….
Careful consideration
of patients
Different vectors?
Monitor patients for
insertion sites
Stem cells?
Immunodeficiencies of T cells and
cell -mediated immunity
 Patients
are susceptible to viral, fungal,
and protozoal infections
 Often exhibit selective defects in Ab
production
 Can be difficult to distinguish from SCID
patients
DiGeorge syndrome
Congenital thymic aplasia – thymus does not develop
normally (neither does parathyroid) 1:4000
 Results from deletion in chromosome 22q11, but is not
inherited
 Few to no mature T cells in periphery
 Symptoms:





Hypocalcemia
Congenital cardiac disease
Recurrent or chronic infections with viruses, bacteria, fungi,
protozoa
Lack of immune response after immunization with T dependent
antigens
Former treatment of DiGeorge
syndrome
 Fetal

thymus graft (<14 weeks gestation)
Why did this result in functional T cells?
Donor fetal thymus provided thymic epithelial cells, and patient’s T
cells had an environment to mature

Why did the T cells “collaborate” poorly with
patient APC?
Patient T cells recognized the MHC of the donor as “self”, not the
patient MHC.
Nude Mice
 Mouse
model for DiGeorge syndrome
T cell deficiencies with normal
peripheral T cell numbers
 Functional,
rather than numerical defect in
T cell population
 Susceptible to opportunistic infections,
high incidence of autoimmune disease
 Autosomal recessive

Deficient expression in:
• ZAP-70 tyrosine kinase (phenotype includes CD8
deficiency and SCID-like symptoms
• CD3e
• CD3g
ALPS
 Autoimmune
Lymphoproliferative Disorder
 Systemic autoimmune disease,
susceptible only to chronic viral infections
 Increased CD4-/CD8- T cells, can develop
B cell lymphomas
 Most patients have a mutation in gene
encoding for Fas (CD95)
Chronic Mucocutaneous
Candidiasis
 Poorly
defined collection of syndromes
characterized by Candida infections of
skin and mucous membranes
 Normal B cell immunity, and normal T cell
immunity (to everything other than
Candida)
 May be inherited, affects predominantly
children
B cell or Ig-associated
Immunodeficiency
 May
be associated with defective B cell
development (absence of all Ig
subclasses) or deficiency in subclass or
class of Ig
 Patients suffer from recurrent or chronic
infections
Brunton’s agammaglobulinemia
 X-linked
infantile agmmaglobulinemia
 1:100,000
 Noticed in infants at 5-6 months of age
 Serious and repeated bacterial infections
 Defect in BTK gene

Pre-B cells cannot develop into mature B cells
 Treatment
consists of IvIg injections, but
chronic lung disease is a problem
Transient Hypogammaglobulinemia
 Normal
number of B cells in blood
 Transient inability to produce IgG
 May be due to deficiency in number and
function of helper T cells
 Does not usually persist past 2 years
CVID





Common Variable Immunodeficiency Disease
Onset 15-35 years, decreased serum IgA, IgG, low to
normal IgM
Pneumonia, bronchiectasis, sinusitis, GI infections
May also have autoantibodies, SLE, higher incidence of
cancer
Caused by failure of B cells to mature to Ab secreting
cells




Class II MHC 6th chromosome
ICOS gene (5%)
TACI gene (15%)
Treatment with IvIg
IgA deficiency
 1:800
incidence
 Lack of serum and mucosal IgA
 Usually asymptomatic
 GI, respiratory disease
 Associated with allergy, autoimmunity
 Etiology unknown, but familial associations
and linkage with CVID
 Broad spectrum antibiotics
Association between CVID and IgAD
Patients with IgA deficiency are usually treated
with broad-spectrum antibiotics. Why is the
injection of IgA not a suitable treatment in these
patients?
A.
B.
C.
D.
E.
Serum sickness will occur
IgA isn’t a good activator of complement, and
thus is useless against bacterial infections
Injected IgA is unlikely to be secreted at the
mucosal immune surfaces
A,B,and C
A and C
Treatment of Ig deficiency
disorders
 IvIg
 Supportive
care (antibiotics)
 No live viral vaccines!
 Complications include malignancies,
autoimmunity
Hyper IgM syndrome
 Mostly
males, rarely females
 Severe respiratory infections, sinusitis,
diagnosed age 1-2
 Very low serum IgG, IgE, IgA, and normal
to elevated IgM
 T cell immunity can weaken with time
 Abnormal germinal center formation
 Complications include malignancy,
autoimmunity
The many causes of Hyper IgM
Duncan Syndrome
 X-linked
lymphoproliferative disease
 Originally observed in 6 maternally related
males of the Duncan family
 T cells can’t regulate B cell growth
 Exposure to EBV results in severe
infectious mononucleosis
 High probability of lymphoma development
 Poor prognosis
Phagocytic dysfunctions
 Affect
the innate and acquired response to
pathogens
 Dysfunction in:


Action required to phagocytize
Migration and adhesion of phagocytic cells
LAD



Leukocyte adhesion deficiency
Autosomal recessive
Group of disorders in which the leukocyte
interaction with vascular endothelium is
disrupted



b subunit of integrins
Selectin ligands
Consequences:



Recurrent soft tissue bacterial infection
Increased blood WBC counts
No pus formation or effective wound healing
BLAD
Early 1990’s – up to
15% of Holstein bulls
and 6-8% of cows
were carriers for
mutated CD18 gene
 Up to 20,000
calves/year potentially
affected
 Screening for the
affected gene reduced
incidence

Chediak-Higashi Syndrome





Autosomal recessive
Abnormal giant granules and organelles in the
cell
Diminished killing of intracellular organisms
(lysosomes and degranulation), leading to
massive infiltration of lymphocytes and
macrophages in liver, spleen, lymph nodes
Strep and Staph main problem – recurrent
infections
Poor prognosis
Chronic Granulomatous Disease





X-linked, autosomal
recessive
Skin, lymph node, lung
infections
High WBC in blood
Phagocytes unable to
complete respiratory burst
Treatments include
antibiotics, antifungals, IFNg
Summary of phagocytic dysfunction
Complement Abnormalities
 Deficiencies
inherited in autosomal
fashion, heterozygotes have 50% of given
complement protein
 Complement is required for:




Opsonization and killing of bacteria
Chemotaxis
B cell activation
Elimination of Ag-Ab complexes
Early complement protein
deficiencies
 C1,
C2, C4 or C3 deficiency
 Pyogenic infections
 Autoimmunity – SLE very common
Late complement protein
deficiencies
 C5-C9
 Prevents
formation of membrane attack
complex
 Gram negative bacterial infections
Diagnosis of immune deficiency
disorders

Medical History




Age at onset
Live vaccines?
Family history
Severity of illness

Physical Exam





Tonsils?
Organomegaly
Palpate lymph nodes
Chart growth
Chest X ray
Lab tests

Phagocyte




Cell surface markers
Bacteriocidal assay
Chemotaxis and opsonization
assays
NK and Macrophage



51Cr
release assays
Cytokine release
B cell function




T cell function





Ig function





Isohemagluttinins
DT, TT response
Anti-pneumococcus
Ig levels
molecular/DNA studies
CD27 memory cells
Nucleic acid enzyme assays
molecular/DNA studies
DTH
Flow cytometry for subsets
PHA/Ag stimulation
TCR spectratyping
Acquired Immunodeficiencies
 Secondary
immune deficiencies that are
the consequences of other diseases





Malnutrition
Chemotherapeutic agents
Deliberate immunosuppression
Untreated autoimmunity
Overwhelming bacterial infection
HIV
HIV binding, replication


Gp120 binds CD4
Coreceptor binding






CCR5 (macrophage tropic)
CXCR4 (lymphtropic)
Penetration of cell
membrane
Transcription of RNA to
CDNA, remains in latent
phase
Activated T cells, viral
replication and release
Macrophages, DC generally
serve as reservoirs
Clinical course of HIV infection

Acute infection




Chronic latent phase



Asymptomatic or flu-like illness
Drop in circulating CD4 cells, CTLs and Ab increase
Seroconversion
Up to 15 years
Low level of viral replication, gradual loss of CD4 cells
Crisis phase



Characterized by unusual malignancies, opportunistic infections,
neurologic sundromes
Activation of virally infected T cells by Ag results in stimulation of
viral transcription and progeny formation, accelerates T cell
death
Also increases viral mutation rate (escape mutants)
Diagnosis of HIV infection
Also, CD4 count
of <200/ml
indicates fullblown AIDS
AIDS associated diseases

Infections

Fungal
•
•
•
•


Candidiasis
Cryptococcosis
Histoplasmosis
Coccidiodomycosis

• Cytomegalovirus
• Herpes simplex
• Progressive multifocal
leukoencephalopathy
Lymphoma
•
•
•
•

Burkitt lymphoma
Diffuse large B cell lymphoma
Effusion-based lymphoma
Primary CNS lymphoma
Carcinoma
• Invasive cancer of the uterine
cervix
Bacterial
Viral
Sarcoma
• Kaposi’s sarcoma
Toxoplasmosis
Pneumocystis
Cryptosporidiosis
Isoporiasis
• Mycobacteriosis (including
atypical Salmonella)

Neoplasms
Parasitic
•
•
•
•



General conditions


HIV encephalopathy and
dementia
Wasting syndrome
Current treatments for HIV

Prevention and control of HIV




Test blood donations
Condom use
HIV+ pregnant women placed on anti-viral therapy
Therapy


AZT (nucleoside inhibitor of reverse transcriptase)
HAART (triple-agent anti-viral therapy, three drugs
from two inhibitor classes)