Transcript Immunodeficiency

Immunodeficiency:
1
• Failure of immune system to protect the host
from infectious agents or malignant cells or from
autoimmune
diseases
is
known
as
immunodeficiency.
• It may be confined to one or more than one
factor or cell of the immune system including
complete absence or deficiency of that element.
• The immunodeficiencies should be suspected in
every
patient, who develops recurrent,
persistent, sever or opportunistic infections.
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• It is either:
• Primary / or / Secondary immunodeficiency.
• 1- Primary immunodeficiency: It is due to an inherited
genetic defect or developmental defect in one of the
genes responsible for expression of an immune factor,
or impairment of function or absence of immune cells.
These defects may interfere with the innate or the
adaptive immunity, affecting cellular or humoral
immune responses.
• These defects may be asymptomatic without giving
clinical disease and discovered accidentally or
expressed as severe clinical conditions at any stage of
patient’s life.
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• 2- Secondary immunodeficiency: It is usually
due to impairment of the immune system by
external factor as:
• Infection e.g.: acquired immunodeficiency
syndrome (AIDS)
• Exposure to chemical agents as chemotherapy
• Exposure to physical agents as nuclear
radiation.
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Primary immunodeficiency (PID):
• There are more than 150 different types of primary
immunodeficiencies (PIDs) in the world.
• Primary T–cells deficiencies:
• It usually leads to Combined Immunodeficiency (CID)
in which there is defect in both T-cell functions and
disruption of antibody immune responses. Examples
for primary T-cells immunodeficiencies:
• Severe combined immunodeficiency (SCID)
• Developmental defects in the thymus
• Wiskott-Aldrich Syndrome (WAS)
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Severe combined Immunodeficiency
(SCID):
• A family of disorders that make most extreme
forms of CID. The defects involved in this
syndrome usually include one of these defects:
• Defective cytokine signaling in T-cell precursors.
• Premature death of the lymphoid lineages.
• Defective V (D) J rearrangement in developing
lymphocytes
• Disruption in pre-TCR or TCR signaling during
development of T-cells.
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• Depending on the underlying genetic defect,
an individual with SCID may have loss of only
T-cells (T-B+) or loss of both T and B cells. In
both cases there will be absence or severe
depression of the humoral and cellular
immune responses, poorly developed thymus
and very low number of circulating
lymphocytes.
• These diseases are either inherited as
autosomal recessive or they are X-linked
diseases.
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• Baby who has SCID will get repeated
infections. The initial manifestation of the
disease is infection by fungi or viruses that are
normally dealt with by the cellular immune
response. The humoral immune response
defects may appear later than 6 months age
because of the presence of passive maternal
antibodies that are received through the
placenta or breast milk.
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The DiGeorge Syndrome (Congenital
Thymic Aplasia)
• The thymic epithelium is derived from the third and fourth
pharyngeal pouch by the sixth week of gestation. Defect is
associated with the deletion of the gene on chromosome
22.
• The T-cell deficiency is variable, depending on how badly
the thymus is affected.
• Affected infants have distinctive facial features; their eyes
are widely separated. They also have congenital
malformations of the heart or aortic arch and neonatal
tetany due to hypoplasia or aplasia of the parathyroid
glands.
• Treatment is by supportive therapy, or thymic epithelial
transplant.
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Wiskott- Aldrich Syndrome (WAS):
• WAS is an X-linked immunodeficiency disease.
• Affected males have small, abnormal platelets with
thrombocytopenia, which may lead to fatal bleeding.
• A boy with WAS develops frequent and severe
dermatitis as well as pyogenic and opportunistic
infections.
• Patient’s serum contains high levels of IgA & IgE,
normal levels of IgG and low levels of IgM.
• Their T cells are defective in function and collaboration
among immune cell is faulty.
•
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2- Primary B-Cells
Immunodeficiencies:
• There is either complete absence of mature Bcells, plasma cells and Igs. Or / selective absence
of certain classes of Igs.
• They have risks for recurrent bacterial infections
with capsulated streptococci, pneumococci or
staphylococci, because Abs. are important for
opsonisation and clearance of these M.Os.
• They have normal immune response to viral or
fungal infections because they usually have
normal T-cell immune response.
•
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X-Linked Agammaglobulinemia (XLA):
• XLA occurs in approximately 1 in 200,000
newborns.
• 85% of cases are due to mutation in a
cytoplasmic Bruton tyrosine kinase (Btk), which is
required in transduction through the BCR.
• Without functioning Btk the development of Bcells in the bone marrow is arrested at the pro-B
to pre-B cell stage and the B-cells in these
patients remain in pre-B cells stage and
Peripheral B-cells are <1%.
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• Inherited as X-linked recessive pattern
immunodeficiency disease and affecting boys
mainly and very rare in girls. About half of
affected individuals get the disease due to
new mutations. Carriers do not have
abnormalities in their immune system, but
they can pass the altered gene to their
children.
• Cover of antibiotics and passive Igs are the
proposed treatment of the disease.
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Common Variable Immunodeficiency
Syndrome:
• There are defects in T cell signalling to B cells
with impairment of B-cells response to Ags.
• There is reduction of one or more isotype of
Abs, but most patients have normal B-cells
number.
• inherited as autosomal recessive or
dominant or due to sporadic mutations. Both
males and females are equally affected.
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• Patients have recurrent bacterial infections.
The disease may appear early in life or may
start late given name: late-onset
hypogamaglobulinemia or incorrectly acquired
hypogamaglobulinemia.
• Patients with CVID should be treated with
intravenous immunoglobulins
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Selective IgA deficiency:
• Frequency of disease is 1:700
• Unknown genetic cause.
• IgA producing B-cells cannot differentiate into plasma
cells.
• Patients have normal other Igs isotypes
• Clinical picture (C.P) is variable from asymptomatic in
70% of cases to severe infections, allergies and
autoimmune diseases. GIT and RT (The primary sites
for production of IgA) are most common sites to get
infected. This wide range of C.P from asymptomatic to
severe cases may be due to ability of some patients to
substitute IgA by IgM on secretary mucosa.
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3- Disruptions of the innate immune
system:
• A- Primary phagocyte deficiencies (PPD)
• These defects are presented by recurrent
bacterial and fungal infections of unusual sites
usually occur in childhood and milder forms in
adulthood.
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Examples:
• Leukocyte Adhesion Deficiency type I:
• This rare disease is due to deficiency of adhesion
molecules CD11a/CD18 (LFA-1), CD11b/CD18
(Mac-1 or CR3) and CD11c/ CD18 (CR4) due to
deficiency of CD18 component in these receptors.
This disease is characterized by impaired
phagocytes migration to the sites of infection in
spite off peripheral leukocytosis.
• Clinically they have repeated gram positive and
negative bacterial infections and fungal infection.
Some of patients die within few years and others
may reach forties.
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Chronic granulomatous disease
(CGD):
• It is due to impairment of the NADPH
(nicotinamide
adenine
dinucleotide
phosphate) oxidative pathway that enables
the phagocyte to produce superoxide radicals
that kill the phagocytosed pathogen. It is
either inherited as X-linked in 70% of cases or
inherited as autosomal recessive in 30% of
cases. Patients suffer from repeated bacterial
and fungal infection with formation of small
granulomatous masses in the infected tissues.
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Chediak-Higashi syndrome (CHS):
• Autosomal recessive disease with impaired
lysosomal transport and storage due to
mutations in the lysosomal trafficking regulator
gene (LYST) that cause impairment in LYST protein
(lysosomal trafficking regulator protein). Patients
with CHS develop neutropenia, impairment Tcells, impaired NK-cells and granulocytes.
Patients presented with recurrent bacterial
infections, blood clotting, pigmentation and
neurologic function, photosensitivity, light colour
hair and skin. Phagocytes produce giant granules
(Diagnostic hallmarks of the disease) but they are
unable to kill microorganisms.
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B- Complement deficiency:
• It is either due to deficiency in complement
activation factor
• Or / deficiency of complement activation
regulator.
• Deficiency of complement activation factor: It
includes deficiency of factors that participate in
the activation of one or more of the three sectors
of the complement activation system (classical
pathway, lectin pathway and the alternative
pathway).
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e.gs:
• 1- C1q deficiency leads to autoimmune diseases as SLE.
• C2, C4 deficiency leads to susceptibility to pneumococcal
infections.
• MASP-2, MBL, and Ficolins deficiency leads to deficiency of
the lectin pathway and increase risk of bacterial infections
as pneumococcal infection, Candida albicans and
autoimmune diseases.
• NB : MASP-2 deficiency transient or permanent may be
protective from death due to to DIC or severe
meningococcal infections.
• MASP-3 deficiency leads to deficiency of the alternative
pathway increase risk of meningococcal infection.
•
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• 3MC syndrome (Mingarelli, Malpeuch, Michels,
and Carnevale syndrome): 3MC syndrome is a
disorder characterized by unusual facial features
and problems affecting other tissues and organs
of the body. 3MC syndrome is caused by
mutations in the COLLEC11 and MASP1 gene.
These genes are thought to help direct the
migration of neural crest cells, which give rise to
various tissues including many tissues in the face
and skull, the glands that produce hormones
(endocrine glands), and portions of the nervous
system
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• . The COLEC11 gene provides instructions for
making a complement activation protein
called CL-11, which is one of the recognition
molecules of the lectin pathway. MASP1 gene
gives arise to three different complement
activation proteins, MASP-1, MASP-3, and
Map-44 by alternative splicing of the gene.
These patients have poor alternative pathway
with high risk to get infection with Neisseria
meningitides.
•
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Deficiency of complement activation
regulation factor:
• These defects usually lead to over activation of
complement system and inflammatory disorders.
• aTypical Hemolytic uremic syndrome: disease
characterized by micro vascular thrombosis,
thrombocytopenia, mechanical hemolytic anemia,
acute renal failure and neurological complications. This
disease occurs due to over activation of the alternative
pathway due to deficiency of FH, FI, MCP-1 or DAF
(decay accelerating factor) complement regulators. The
first choice of treatment is Eculizumab (humanized
anti-C5 monoclonal antibodies).
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• Paroxysmal nocturnal hemoglobinourea
(PNH): characterized by destruction of RBCs by
complement MAC due to defect in
complement regulators as protectin and DAF.
Treated by Eculizumab.
•
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• Hereditary angioedema (HAE): autosomal
dominant inherited disease characterized by
deficiency of C1INH characterized by over
activation of the classical pathway and to lower
extent the lectin pathway of the complement
system. Signs and symptoms begin around
puberty. These patients have recurrent swellings
in different places of their bodies which may be
fatal if occur in vital organs or respiratory tract.
Treated by giving iv C1INH
•
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Diagnosis of immunodeficiencies:
• Awareness of the condition is most important part of
the diagnosis and treatment of PIDs. These tests can be
used for diagnosis and assessment of PIDs:
• Complete blood counts and blood film.
• Serological tests for measurement of levels of
cytokines, immunoglobulins and complement factors.
• Bone marrow aspirates and examination
• Chromosomal analysis and gene study.
• Functional tests for immunological cells as T-cells, Bcells and macrophages.
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Treatment of Primary
immunodeficiencies:
• The treatment options of PID include:
• Replacement of missing protein:
• As: Immunoglobines concentrates and
monoclonal Abs given i.v. Or S.C. IgG level
around 5mg/ml can prevent infections.
• IFN- γ replacement approved to be of benefit in
CGD
• Recombinant adenosine deaminase in SCID.
•
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• Replacement of missing cell type lineage: by
bone marrow transplantation
• Replacement of missing gene: gene therapy
when single gene is affected
• Supportive therapy as effective preventive and
therapeutic antibiotics, surgical drainage of
abscess, vaccination and hygiene control.
• Eculizumab for treatment of complement over
activation due to regulator deficiency.
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Secondary immunodeficiencies
• The immune system can be adversely affected by
a variety of extrinsic factors including:
• Immunosuppressive drugs.
• Exposure to harsh environmental conditions as
radiation.
• Hereditary disorders other than primary
immunodeficiencies.
• Acquired metabolic disorders such as diabetic
mellitus.
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• Perhaps the most well known secondary
immunodeficiency is Acquired Human
Immunodeficiency Syndrome (AIDS) caused by
Human Immunodeficiency Virus (HIV)
infection.
• The most common cause of immunodeficiency
worldwide is severe malnutrition, which
affects as much as 50% of the population in
some impoverished communities.
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• Extremes of age and neonatal prematurity
increase susceptibility to infection
• The abnormalities of the immune system
induced by secondary immunodeficiencies
affect both the innate and the adaptive
immunity. Treatment of the primary condition
often results in the improvement of the
compromised immune components of the
disease complex.
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Immunosenescence:
• It is a decline of the immune response due to aging
• Characterized by:
• Weakness of the T cell response with reduced delayed type
hypersensitivity reaction.
• Decrease in immunoglobulins production against many
pathogens
• Auto Abs against self antigens are formed but autoimmune
diseases are less common
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• Declined responses to vaccines, and may not
develop protective immunity after influenza
vaccine
• 5-Allergic disorders and transplant rejection are
less common
• 6- Increases of susceptibility to infections like
respiratory tract infection, and UTI. TB and
Herpes Zoster may be reactivated.
• 7- Decline or absence of leukocytosis &pyrexia
can be noticed during infection.
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HIV infection and Acquired
immunodeficiency syndrome:
• HIV stands for human immunodeficiency virus. It
is retrovirus. It attacks the body’s immune
system, specifically the CD4+ T-cells. Over time,
HIV reduces the number of CD4+ T-cells in the
body. Opportunistic infections or cancers will be
very common and fatal due to a very weak
immune system.
• No effective cure exists for HIV. But with proper
medical care, HIV can be controlled.
• How the virus invades and multiplies inside the
CD4+ cells:
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• This process includes two stages:
• First stage includes the integration of viral
genome into the cellular DNA as following:
• HIV gp120 receptor binds to CD4 on target cells
• HIV gp41 receptor fuses with the cell membrane
receptor CXCR4 or CCR5.
• Viral genome and enzymes enters the cells
• Viral genome and enzymes will be released inside
the cells after removal of all nuclear proteins
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• Reverse transcription of viral single stranded
RNA (ssRNA) by the viral reverse transcriptase
enzyme occurs to give DNA and form RNADNA hybrid
• Degradation of the viral RNA and completion
of the HIV double stranded DNA (dsDNA OR
called cDNA).
• The viral DNA will be trans located into the
nucleus and integrated into the cell genomic
DNA by the help of the viral integrase enzyme.
• (please refer to figure: 1(A))
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Figure 1:
a- insertion of the viral genome into the
nuclear DNA
b- synthesis and release of the viral
particles
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• The second stage includes the synthesis of the
new viral genome:
• Transcription of proviral DNA into genomic
ssRNA
• Viral RNA is exported to cytoplasm
• (A)- production of viral precursor proteins by
cell ribosomes (B)- viral enzymes change the
precursor enzymes into viral proteins
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• Viral RNA and protein will assemble beneath
the host cell
• mbrane where gp120 and gp41 are inserted.
• (A)- the membrane buds out forming viral
envelope (B)- release of viral particles to
outside the cells
(Please refer to figure 1 (B))
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Figure 1:
a- insertion of the viral genome into the
nuclear DNA
b- synthesis and release of the viral
particles
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Patients with AIDS are susceptible to:
• Patients with AIDS are susceptible to:
• Fungal infections: Candidiasis,
Coccidioidomycosis, Cryptococcosis,
Histoplasmosis, and Pneumocystis carinii
pneumonia (PCP)
• Parasitic infections: Cryptosporidiosis, chronic
intestinal (greater than one month's duration)
and also extra intestinal infection, Toxoplasmosis
of brain, Cystoisosporiasis, chronic intestinal
(greater than one month's duration) with extra
intestinal infections.
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• Viral infections: Cytomegalovirus diseases (particularly
retinitis) (CMV), Herpes simplex (HSV): chronic ulcer(s)
(greater than one month's duration); or bronchitis,
pneumonitis, or esophagitis
• Bacterial infections: Tuberculosis (TB), Pneumonia
(recurrent), and Salmonella septicemia (recurrent).
• Cancers: Kaposi's sarcoma (KS) and Invasive cervical
cancer
• Brain white matter diseases as Progressive multifocal
leukoencephalopathy
•
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