Transcript trouble thymique

Immunodeficiency
Results from the absence, or failure of normal
function of one or more elements of immune
system.
• involve abnormalities of T or B cells, the cells
of the adaptive immune system.
• or abnormalities of elements such as
complements or phagocytes, which act on
non-specifically in immunity
Immunodeficiency can be divided into
1. Primary immunodeficiency disorderscongenital immunodeficiency
(genetically determined)
2. Secondary immunodeficiency disorders
(acquired immunodeficiency)
Arise as complication of infection,
malnutrition, aging, side effects of
immunosuppressive drugs and irradiation
B-cell deficiency
A. X- linked hypogamaglobunemia or (Bruton’s
Agammaglobulinaemia)
Failure of pre-B cells to differentiate into B cells.
due to mutation in the gene encoding Tyrosine
kinase an important signal transduction protein
• CMI is normal but very low levels of all
immunoglobulin
• and absent of B cells in young boys
• Female carriers are immunologically normal
Present with pyogenic infections
(S. aureus, S. pyogenes , S. pneumoniae,
N.meningitides, H.influenzae ) which cause
infection of the middle ear (otitis), sinuses
(sinusitis) and lungs (pneumonia or
bronchitis),
But in some instances infections can involve
the bloodstream or internal organs as well.
Patients with XLA are prone to develop
infections because they lack antibodies.
Most patients with
agammaglobulinemia have very
small tonsils and lymph nodes
This is because most of the bulk of
tonsils and lymph nodes is made up
of B-lymphocytes.
In the absence of B-lymphocytes,
these tissues are reduced in size.
Diagnosis
• Agammaglobulinemia should be considered in
any child with recurrent or severe bacterial
infections, particularly if the patient has small
or absent tonsils and lymph nodes.
• The first screening test should be an
evaluation of serum immunoglobulins
• If the serum immunoglobulins are low or if
the physician strongly suspects the diagnosis
of agammaglobulinemia,
• the number of B-cells in the peripheral blood
should be measured.
• A low percentage of B-cells (nearly absent) in
the blood is the most reliable laboratory
finding in patients with either XLA
• pts with XLA can be given some of the
antibodies that they are lacking.
B. Selective immunoglobulin
deficiencies
IgA deficiency
• characterized by an undetectable level of
immunoglobulin A (IgA) in the blood and
secretions but no other immunoglobulin
deficiencies.
• Patients presents with weakened mucosal
defenses thus;
• (a) recurrent sinus and lung infections
• (b) Diarrhea.
• IgA deficiency is caused by the failure
of heavy chain gene switching
• Pts with selective IgM and IgG also
have recurrent pulmonary infection
caused by pyogenic bacteria
• H. influenza S. pneumonia and S.
aureus
T cell deficiency
A. THYMIC HYPOPLASIA
(DIGEORGES SYNDROME)
• Is a congenital malformation affecting the 3rd and
4th pharyngeal pouches.
• These structures give rise to the
• (1) Thymus
• (2) parathyroid glands and,
• (3) portion of the lip, ears, and aortic arch.
• Both thymus and parathyroid fail to develop
properly.
• The thymus is usually rudimentary
• and T cells are deficient or absent in
circulation.
• Thus infants with this deficient are
vulnerable to viral, fungal or protozoan
infections.
• Also defects to the face, ears, heart and
great vessels.
• Management
• Transplantation of fetal thymus may
reconstitute T cell immunity
• thymus from a child < 14 wks should
be used to avoid Graft Versus Host
(GVH) reaction
B. Chronic mucocutaneous candidiasis
• Skin and mucous membrane of children are
infected with C.albicans
• which is non pathogenic member of normal
flora.
• These children have T cell specific deficiency
to this organism
• other T cell and B cells are normal.
• Treatment include antifungal drugs
C. HYPER IgM SYNDROME
• Present with recurrent pyogenic bacterial
infection
• pts have high conc. of IgM
• but very little IgG, IgE & IgA
• They have normal number of B and T cells
• The mutation is in the gene encoding the
CD40 ligand in the CD4 positive helper T
cells
The T cell have defect in the surface protein
(CD40 ligand) that interact with CD40 on the B
cell surface.
The failure to properly interact with CD40
result in inability of the B cells to switch from
the production of IgM to other classes of
antibodies
• recurrent pyogenic bacterial infections begins
early in life
• Treatment- gamma globulin
D. Interleukin-12 Receptor Deficiency
• Interleukin-12 (IL-12) is involved in cellular
immune responses against intracellular
pathogens by promoting the generation of TH1
cells
• The absence of the receptor prevents IL-12 from
initiating a Th-1 response, which is required to
limit mycobacterial infections
• and lead to disseminated mycobacterial
infections
Combined B cells and T cells deficiencies
A. SEVERE COMBINED IMMUNODEFICIENCY (SCID)
defects in both humoral and cell mediated
response.
infants are susceptible to:
• Severe infections (viral, bacterial, fungal and
protozoa)
• Opportunistic infections with;
• candida , P. jeroveci, cytomegalovirus,
pseudomonas.
• Occur in early infancy 3 months of age
• In some children the B & T cells are absent
• in others the number of cells is normal but they
do not function properly
• Immunoglobulin levels are very low and tonsils
and lymph nodes are absent
• Pneumocysts pneumonia is the most common
presenting infection in these infants
• infection caused by C .albicans and viruses such
as varicella zoster and cytomegalovirus and
respiratory cycytial virus are common and often
fatal.
There are different forms of SCID;
Cytokine receptor mutation form
ADA deficiency (adenosine deaminase)
Failure of expression of class II MHC
molecule.
Cytokine Receptor Mutation Form
Severe defect is in the T cell
compartment,
with secondary impairment of humoral
immunity and IL-2,4,7,11,15 .
patient have functional deficient of
which are required for T cell
development hence lack of T cells.
Adenosine deaminase (ADA)
Deficiency;
• is caused by mutations in the ADA gene
• that provides instructions for producing
the enzyme adenosine deaminase
• This enzyme is most active in lymphocytes
• which protect the body against harmful
invaders, such as bacteria and viruses
• The function of the adenosine deaminase
enzyme is to eliminate a molecule called
deoxyadenosine, which is generated when
DNA is broken down.
• Adenosine deaminase converts
deoxyadenosine, which can be toxic to
lymphocytes, to another molecule called
deoxyinosine that is not harmful.
• Mutations in the ADA gene reduce or
eliminate the activity of adenosine
deaminase
• and allow the buildup of
deoxyadenosine to levels that are toxic
to lymphocytes.
• Immature lymphocytes in the thymus are
particularly vulnerable to a toxic buildup of
deoxyadenosine.
• These cells die before they can mature to help
fight infection.
• The loss of infection-fighting cells results in
the signs and symptoms of SCID.
Management
Bone marrow transplantation can be helpful
 Injections of ADA conjugate reduce the
number and severity of infections
Gene therapy where a retroviral vector
carrying a normal copy of ADA gene is allowed
to infect the patient borne marrow cells the
ADA gene function within some of these
genes and the pts immune status improved
Class II MHC Molecule Failure
• impairs the function of CD4 helper T cell
because they can only recognize antigens
presented by the class ll molecule.
• consequently both cell mediated and T
dependent are impaired.
SCID patient is treated with
• -Bone marrow transplantation.
• -Gene therapy
B. WISKOTT-ALDRICH SYNDROME
• Recurrent pyogenic infection, eczema and bleeding
caused by thrombocytopenia
• Appears during 1st year of life
• it is x- linked disease
• Important defect is failure to mount an IgM
response to the capsular polysaccharide of bacteria
such as pneumococci
• The defect is in T-cells to which fail to provide help
to B- cells.
• The mutant gene encodes a protein involved in
actin filament assembly.
• Bone marrow transplant may be helpful
C. ATAXIA- TALANGIECTASIA
•
•
•
•
•
is a rare inherited disorder
affects the nervous system,
immune system,
and other body systems.
characterized by progressive difficulty with
coordinating movements (ataxia)
• beginning in early childhood before age 5.
• Affected children develop difficulty walking,
problems with balance and hand
coordination, involuntary jerking
movements (chorea),
• muscle twitches (myoclonus), and
• disturbances in nerve function
(neuropathy).
• slurred speech and trouble moving
their eyes to look side-to-side
(oculomotor apraxia).
•
• Disease caused by mutation in
the genes that encode DNA
repair enzymes.
• Treatment designed to correct
immunodeficiency has not been
successful
COMPLEMENT DEFFICIENCY
A. HEREDITARY ANGIO EDEMA
Caused by a deficiency of C1 Inhibitor
• In the absent of Inhibitor C1 continuous to act
on C4 to generate C4a and subsequently
additional vasoactive components such as C3a
and C5a
• this lead to capillary permeability and edema
in several organs
• laryngeal edema can be fatal
• Steroid drugs can be useful
B. Recurrent infections
• Patients with deficiency in C1,C3,C5 have an
increased susceptibility to bacterial infections.
• Those with reduced level of (C6,C7,C8) are
prone to recurrent Neisseria gonorrhea & N.
meningitides infections.
• Inherited deficiency of C1q, C2 and C4
increase risk of immune complex mediated
disease
by impairing the clearance of immune
complexes from circulation .
Decay-accelerating factor (DAF)
deficiency
• Causes Paroxysmal Nocturnal
Hemoglobinuria
• is a rare disease
• Characterized by episodes of brownish urine
(hemoglobinuria), esp. upon arising
• There is a deficiency of decay-accelerating
factor (DAF) on the surface of blood cell
precursors, leading to an increased activation
of complement , hence haemolysis
• Decay-accelerating factor (DAF, CD55), an
intrinsic membrane glycoprotein of red cells,
granulocytes, platelets and lymphocytes,
• DAF functions as a complement regulatory
factor
• by inhibiting assembly and accelerating
dissociation of C3 and C5 convertases of the
classical and alternative pathways
• There is a defect in the gene for the
molecules that anchor DAF and other proteins
to the cell membrane.
• No specific treatment.
• Give Iron for the anemia, and prednisone
can help.
Phagocyte deficiencies
A. Chronic granulomatous disease
• Patients are prone to opportunistic diseases
• Appears at 2yrs of age
• Is due to defect in the intracellular
microbicidal activity of neutrophils as a result
of lack of NADPH oxidase activity or similar
enzymes
• as a result no hydrogen peroxide or
superoxide are produced ( i.e. no oxidative
bust occurs) and the organism although
ingested are not killed.
treatment
• Aggressive treatment with antibiotic
• Gamma interferon reduce the frequency of
recurrent infections
B . Chediak-higashi syndrome
• recurrence pyogenic infections caused by
staphylococcus & streptococcus
disorder that arises from a mutation of a
lysosomal trafficking regulator protein,which
leads to a decrease in phagocytosis
Diagnosis
• The diagnosis is confirmed by bone marrow
smears that show "giant inclusion bodies" in the
cells that develop into white blood cells
(leukocyte precursor cells).
• There is no specific treatment for Chédiak–
Higashi syndrome.
• Bone marrow transplants appear to have been
successful in several patients.
• Infections are treated with antibiotics and
abscesses are surgically drained when
appropriate.
C. Job`s syndrome
(hyper IgE syndrome)
• Job’s syndrome is a rare condition
which affects both males and
females with symptoms usually
beginning in childhood.
• The most common features are
eczema, increased susceptibility to
infections and markedly raised levels
of IgE
• Patients with this syndrome have recurrent
“cold” staphylococcus abscesses, eczema
skeletal effects and high level of IgE
• Defect is the failure to produce gamma
interferon by helper T- cells
which reduces the ability of macrophages to kill
bacteria
this lead to an increase in Th2 cells and
consequences a high IgE level
Job`s syndrome
Treatment of Hyper IgE Syndrome
• Therapy of HIES remains largely supportive.
Antibiotic prophylaxis used against recurrent
respiratory infections.
• skin care and prompt treatment of skin
infections
• When the eczema is severe, topical
moisturizing creams can help
SECONDARY IMMUNODEFICIENCIES.
• More common than primary.
• acquired from either iatrogenic cause or
infection.
• Patients receiving immunosuppressive drugs for
prevention of graft rejection or
• Rx of autoimmune diseases.
• Can be from malnutrition
• Cancer
• B- CELL DEFICIENCY
• A COMMON VARIABLE HYPERGAMMAGLUBULINEMIA
• Pts present with recurrent infections caused by
pyogenic bacteria
• The infection occur btn the age 15 and 35yrs
the B- cells inability to synthesize IgG and other
immunoglobulin is greatly reduced
• the cause is unknown but appears to be due to
defective in T-cell signaling
• Intravenous gamma globulin given monthly
reduce number of infection
B. Malnutrition
• Can reduce the supply of amino acid and
thereby reduces the synthesis of IgG this
predispose to infection by pyogenic bacteria
T-cell deficiency
• A. Acquired immunodeficiency syndrome
reduces helper T cells number by retrovirus
infection
• which infect and kill cells bearing the CD4
protein as a surface receptor
Complement deficiency
• A. Liver failure caused alcoholic or by chronic
Hepatitis B or C
• can reduce the synthesis of complement
protein by the liver to level that pyogenic
infection can occur
• B Malnutrition
• severe malnutrition can reduce supply of
amino acids and thereby reduce the synthesis
of complement protein by the liver this
predispose to infection
Phagocyte deficiency
• A. Neutropenia
• patients present with severe infection caused
by pyogenic bacteria such as S. aureus, S.
pneumonia and enteric gram negative rods
• neutrophils count below 500/µL predispose
to these infection
• Common cause of neutropenia include
cytotoxic drugs
• Ciprofloxacin is used to try to prevent
infections