Immunology

Immunodeficiency

Marah Mubita
University of Zambia,
School of Medicine,
Pathology and Microbiology
Dept.
• Immunodeficiency full or partial impairment of the
immune system.
• This leaves the patient unable to effectively resolve
infections or disease.
• Immunodeficiency disorders can either be primary or
secondary in nature
• Primary immunodeficiencies are the result of genetic
defects
– Usually present at birth and diagnosed in childhood
– Most of us have some form of PID genetics and
environment affect manifestation
• Secondary immunodeficiencies are caused by
environmental factors, such as infections or
malnutrition.
Primary immunodeficiency
• There are >300 types of primary immunodeficiency
• They are sometimes caused by single-gene mutations
• They are more often caused by unknown genetic
susceptibility combined with environmental factors.
• Although some PIDs are diagnosed during infancy or
childhood, many are diagnosed later in life.
• PIDs are categorised based on the part of the
immune system that is disrupted.
– B cell immunodeficiencies
– T cell immunodeficiencies
– Phagocyte immunodeficiencies
– Complement immunodeficiencies
– Mixed immunodeficiencies
B-cell Immunodeficiencies
• B-cells are the key cell type for humoral immunity of
the adaptive immune system
• Their main role is to produce antibodies which
highlight microbes making phagocytosis easier
• Mutations in the genes that control B cells can result
in the loss of antibody production
• These patients are at risk of severe recurrent
bacterial infections.
• Onset during 6 － 12 months of age
• High risk of allergy and autoimmune diseases
 X-linked Agammaglobulinaemia
• Aka Bruton’s agammaglobulinemia
• Is an X-linked recessive disease
• Characterised by a defect in the B-cell tyrosine kinase (BTK)
gene
• Which leads to an inability for B cells to differentiate and
mature into functional cells
• Consequently, individuals present with severe and recurrent
infections
• Especially due to encapsulated bacteria
– Streptococcus pneumoniae, Klebsiella pneumonia, group B
streptococci, Escherichia coli, Neisseria meningitides and Haemophilus
influenzae.
• This tends to present after 6 months of life when maternal
immunoglobulin begins to wane.
1.Reduction of immunoglobulin levels. Generally serum IgG < 200mg/dL, IgM and IgA <
20mg/Dl.
 Selective IgA deficiency
• Is the most common primary immunodeficiency
• There is an isolated deficiency in immunoglobulin A
• The cause is unknown, and often cases
are asymptomatic
• It can cause respiratory infections and chronic
diarrhoea
• Additionally some individuals may have severe
anaphylactic reactions to IgA when receiving a blood
transfusion.
 Hyper-IgM syndrome
• Is an X-linked recessive disorder caused by a defect in
the CD40 ligand
• This prevents class switching
• B cells can’t switch the production of IgM antibodies
to IgG, IgA or IgE types
• It causes recurrent respiratory, gastrointestinal, and
sinus infections
• There are usually normal or elevated levels of IgM
but decreased levels of IgG and IgA.
Common variable immunodeficiency

• An umbrella term for antibody deficiency where the

genetic cause is unknown
• There is a genetic mutation, but an infectious trigger
is required for it to manifest.
• B cells are of a normal phenotype, but unable to
differentiate into plasma cells
• There are low concentrations of all classes of Igs, but
particularly IgG, IgA and IgM.
• Has a late onset typically presenting in adulthood
around the age of 20-35 with recurrent, severe
sinopulmonary infections.
T- cell Immunodeficiencies
• T cell deficiency can be due to reduced T cell counts,
or impaired activity
• This predisposes the sufferer to severe infections by
intracellular parasites - bacteria and viruses
• This can present with failure to thrive and/or
diarrhoea in early life
• It is also associated with mucosal infection by yeasts
such as candida
 DiGeorge syndrome
• Autosomal dominant condition
• Due to gene deletion in chromosome 22 q 11.
• This results in complete or partial absence of thymus
• This causes a defect in T-cell clonal selection and
maturation
• Associated with increased susceptibility to viral
infection
• Also results in reduced active T cell production
Phagocyte immunodeficiencies
• The most effective phagocytic cells in humans are
macrophages and neutrophils
• Mutations typically affect the ability to phagocytose
and destroy pathogens effectively
• These patients have largely functional immune
systems but certain bacterial and fungal infections
can cause very serious harm or death.
Chronic granulomatous disease
• Its an X-linked or autosomal recessive inherited
disorder
• There is defective production of reactive oxygen
species due to a defective NADPH oxidase or
cytochrome b oxidase enzymes
• This decreases the oxidative burst in phagocytes
• This disease presents in childhood with recurrent
infections and granuloma formation
• 2/3 onset before 1 year, most under 6 months of age
• Presents mostly as skin infection and abscess
 Chediak Higashi syndrome
• Autosomal recessive disorder
• Affecting Chromosome 1 -Lysosomal trafficking
regulator (LYST) Gene
• There is usually a defect in fusion of lysosome to
phagosomes
• And also a defect of release of cytotoxic granules
• Associated with increased susceptibility to pyogenic
bacteria.
• As well as reduced ability of phagocytes to kill
ingested microbes
• Decreased functions of NK cell Cytotoxicity
• Risk for development of Lymphoma.
 Congenital neutropenia
• It can be inherited in an X-linked, autosomal
recessive or autosomal dominant manner
• Its characterised by a decreased neutrophil count
• causes recurrent life-threatening bacterial infections
– Gingivitis
– Otitis media
– Respiratory infections
Leukocyte adhesion deficiency type 1
• Its an autosomal recessive inherited disorder
• causes an impairment of neutrophil function
• An absent CD18 protein affects the margination of
neutrophils
• This causes them to accumulate in the blood without
being able to leave the bloodstream to fight infection
• It presents with recurrent bacterial infections
especially of skin, mucosa and delayed separation of
the umbilical cord.
Complement immunodeficiency
C1 esterase inhibitor deficiency
• Aka Hereditary angioedema
• its an autosomal dominant inherited disorder
• Leads to sudden uncontrolled activation of
complement and bradykinin pathways
• This leads to recurrent spontaneous attacks of non-
itchy angioedema
• It can be life-threatening if affecting the airway
 C3 deficiency
• Causes impaired opsonisation due to reduced levels
of the opsonin C3b
• This results in recurrent severe childhood infections
by encapsulated bacteria such as Neisseria
meningitidis and Haemophilus influenzae
• C3 deficiency is also associated with autoimmune
diseases and type III hypersensitivity reactions
 Terminal complement deficiency
• It is autosomal recessive disorder
• It affects the production of C5-C9 complexes
• Causes an inability to produce antigen-antibody
complexes
• Leads to defective opsonisation and phagocytosis
• There is an increased risk of infection especially
Neisseria meningitidis and Neisseria gonorrhoeae.
Secondary immunodeficiency
(SID)
• SIDs are more common than PIDs and are the result
of a primary illness
• Contributing factors include HIV, malnutrition or
some drug regimens
• Most SIDs can be resolved by treating the primary
condition
• Usually classified as
– Malnutrition SIDS
– Therapeutic SIDS
– Malignant or tumour associated SIDS
– Infectious SIDS
 Malnutrition
• Protein-calorie malnutrition is the biggest global
cause of SIDs
• It can affect up to 50% of the population in some
communities in the developing world
• T cell numbers and function decrease in proportion
to levels of protein deficiency
• This leaves the patient particularly susceptible to
diarrhoea and respiratory tract infections
• This form of immunodeficiency will usually resolve if
the malnutrition is treated.
 Therapeutic
• There are several types of medication that can result
in secondary immunodeficiencies
• These drugs also perform critical roles in certain
areas of healthcare
• Immunosuppression is a common side-effect of most
chemotherapies used in cancer treatment
• Corticosteroids play a very crucial role in
inflammatory as well as autoimmune conditions
• The immune system usually recovers once the drug is
withdrawn
 Malignant
• Multiple myeloma
– Increased polyclonal B cell activation non-
specifically
• Lymphoma (HK)
– Uncontrolled proliferation of B lymphocytes (E.B
virus)
• Chronic lymphocytic leukemia
– Reduced production of Immunoglobulin.
 Infectious
• Schistosoma species
– Enzymatic degradation of immunoglobulins
• Herpesvirus
– inhibits MHC class I maturation within E.R
• CMV
– Interferes with TAP of E.R. Redirects MHC I into cytoplasm rather
than to cell surface
• Chlamydia
– prevents phagosomes-lysosomes fusion
• Staphylococcus
– Kills phagocytes by its toxins, Protein A prevents opsonization
• Mycobacterium
– Kills phagocytes, Prevents phagosome-lysosome fusion and
Inhibits oxidative degradation within phagosome.
Acquired immunodeficiency syndrome
• Commonly called AIDS
• Results from infection with the lentiviruses HIV‐1 or
HIV‐2
• HIV‐1 is much more prevalent worldwide
• HIV‐1 infects CD4+ cells, including CD4+ T‐cells,
macrophages, and dendritic cells.
• Once the T cell count is less than 200/ml of blood
symptoms of AIDS manifest
• Patients are at high risk of recurrent opportunistic
infections that will eventually lead to death
 Common HIV associated infections

• Bacterial – Tuberculosis, Typhoid, Gonorrhea etc.

• Viral – CMV, HSV, EBV, HHV, HBV etc.
• Fungal/ Mycotic – Candidiasis, Cryptococcosis,
Histoplasmosis, Aspergillosis
• Parasitic – Toxoplasmosis, Cryptosporidiosis
• Malignancies – Kaposi’s sarcoma, Non-Hodgkin’s
lymphoma
Principles of management
• Diet
• Avoidance of pathogens (“germ-free” care)
• Antibiotics
– Use in acute illness
– Prophylactic
• Avoid whole blood transfusion in combined
immunodeficiency disorder
• Avoid live virus vaccines and BCG
• Immunoglobulin replacement therapy
• Interferon gamma for phagocyte disorders and
transfusion