IMMUNODEFICIENCY DISEASES
– INHERITED & ACQUIRED
Prof. S. S. Taiwo
Learning Objectives
• Students should have good theoretical understanding of
overview of immunodeficiency disorders with respect to;
• Types of immunodeficiency disorders
• primary/inherited/congenital and secondary/acquired
• humoral/cell-mediated/combined/innate immune system disorders
• Genetic basis underlying primary immunodeficiencies and factors
contributing to secondary immunodeficiencies
• Clinical manifestations and diagnosis of immunodeficiency disorders
• Management of immunodeficiency disorders
Introduction
• Immunodeficiency is a state in which the ability of the immune
system is compromised (or entirely absent) to respond to foreign
antigens (especially infectious diseases and cancers).
• This state may also affect the normal response to ‘self’ antigens with
tendency to development of autoimmune disorders
• Immunodeficiency disorders can be grouped based on:
• Origin of the disorder
• primary/inherited/congenital
• Secondary/acquired
• Component of the immune system affected
• specific immunodeficiencies - abnormalities of the adaptive immune system (B & T cells)
• non-specific immunodeficiencies - abnormalities of the innate (non-specific) immune system
PRIMARY IMMUNODEFICIENCIES
• There are over 150 different primary immunodeficiency
disorders identified to date.
• All are relatively rare genetic defects that affect the
immune cells and are usually hereditary
• They usually present at birth or evident during infancy or
childhood, however, some disorders such as common
variable immunodeficiency (CVI) are not recognized until
adulthood
Types of primary immunodeficiencies
• Adaptive immune system deficiency disorders
• Humoral (B-lymphocytes)
• Cellular (T-lymphocytes)
• Combined (B and T-lymphocytes)
• Innate immune system deficiency disorders
• Phagocyte disorders
• Complement disorders:
• Toll-like receptors & TLR pathways deficiency
(A) Primary adaptive immune deficiency disorders
1. Humoral immune system deficiency disorders
i. Common variable immunodeficiency (CVID)
• In CVID, there is failure of B-lymphocyte maturity (qualitative but not
quantitative defect) and thus they cannot produce immunoglobulins.
In some people with this disorder, T lymphocytes also malfunction
• Mutations occur in multiple genes (BAFFR, ICOS, TACI/TNFRSF13B,
CD19, CTLA-4) leading to deficiency in;
• normal B/T-cell maturation/development
• cell surface receptors involved in signal transduction necessary for B cell
development and function
• Ig isotype switching (class switch recombination CSR)
• These mutations can be inherited but more often, they can occur
spontaneously as somatic hypermutation (SHM) defects
ICOS= Inducible T cell Costimulator; APRIL = A PRoliferation Inducing Ligand; BAFF = B cell activating factor; BR3 = BAFF receptor (BAFFR or TNFRSF13C); BCMA = B cell maturation antigen (TNFRSF17);
TACI = transmembrane activator and CAML interactor (TNFRSF13B); CAML = calcium modulator and cyclophilin ligand
• Clinical manifestations:
• condition is usually diagnosed between the ages of 20 and 40 years.
• recurring sinus and lung infections, particularly pneumonia, are common, with
chronic cough, haemoptysis and/or difficulty with breathing.
• diarrhea may occur, and spleen may enlarge.
• up to 25% of people with CVID develop autoimmune disorders
• mostly people have a normal life span
• Laboratory diagnosis
• measure baseline serum immunoglobulin levels
• response of individuals to vaccination – measure immunoglobulin levels
• Treatment
• immune globulin (antibodies obtained from the blood of people with a normal
immune system) is given throughout life to provide the missing immunoglobulin.
Give IV (once a month) or subcutaneously (once a week or once a month).
• antibiotics are promptly given to treat infections
• autoimmune disorders are treated as needed with drugs that suppress or modify
the immune system's activity (such as rituximab, etanercept, infliximab or
corticosteroids)
ii. Selective immunoglobulin deficiency (SID)
• SID results in a low level of one type (class) of antibody
(immunoglobulin) but levels of other Igs are normal
• most commonly affected class is IgA deficiency
• is inherited though mode of inheritance is unknown
• Selective IgA deficiency
• is a low level of immunoglobulin A (IgA)
• in some cases, caused by a mutation in a specific gene (TNFRSF13B/TACI) that
codes for TACI (transmembrane activator and CAML interactor) protein also
known as tumor necrosis factor receptor superfamily member 13B
(TNFRSF13B) or by a drug (phenytoin or sulfasalazine)
• familial history increase the risk by about 50 times
• Clinical manifestations
• mostly no symptoms are observed, but some have chronic lung infections,
sinusitis, and other disorders.
• susceptible to pyogenic infection
• life span is usually unaffected
• patients tend to develop immune complex disease
• Diagnosis
• measure serum levels of immunoglobulin levels
• Treatment
• antibiotics to treat or sometimes to prevent infections
• usually, no treatment is needed
iii. Transient hypogammaglobinaemia of infancy (THI)*
• At birth, the immune system is not fully developed. Most of the Igs are transferred
via the placenta from mother. In normal infants, Ig synthesis begins at 3 months
• In THI, production of normal amounts of Igs in infants is delayed in this disease,
mainly affecting IgG synthesis. As a result, Ig levels become low starting at age 3 to
6 months and return to normal at about age 12 to 36 months. It is common among
premature infants because they receive fewer Igs from the mother
• THI rarely leads to serious infections: just sinus, lung, or digestive tract infections,
candidiasis and meningitis
• Measure serum levels of immunoglobulins to confirm
• THI may last for months to a few years but usually resolves without treatment
iv. X-linked agammaglobinaemia (XLA)
• XLA is an X-linked inherited agammaglobinaemia due to mutations in BTK
gene on the X (sex) chromosome (Xq21.3 - 22) which affects boys.
• Also known as Bruton agammaglobinaemia named after the man who
described a critical enzyme, tyrosine kinase, involved in maturation of
pro-B cells to differentiating B cells.
• BTK mutations result in no matured B lymphocytes and very low levels of
Igs (or no Igs at all)
• Clinical manifestations:
• risk of developing infections in the joints (infectious arthritis), irreversible
widening due to chronic inflammation of the airways (bronchiectasis), and certain
cancers
• *BTK – Bruton Tyrosine Kinase
Early stages of B-cell differentiation can be identified by the status of the immunoglobulin
genes and by the cell surface markers CD34, CD19, and surface immunoglobulin (sIg).
From: Conley ME. Genes required for B cell development. J Clin Invest. 2003;112: 1636-8.
v. Hyper-IgM syndrome
• X-linked hyper-IgM syndrome with CD40 ligand deficiency
• mutation in CD40 ligand (CD40L) gene in T cells results in failure of B-cell activation.
• similar presentations to X-linked agammaglobinaemia but with severe neutropaenia,
lymphoid hypoplasia and more frequent Pneumocystitis jirovecii pneumonia and
cryptosporidiosis
• Hyper-IgM syndrome with CD40 deficiency
• mutation in the CD40 gene in B cells results in failure of B-cell activation (by T cells)
• autosomal recessive inheritance
• similar presentations to X-linked agammaglobinaemia but with neutropaenia and
lymphoid hypoplasia
• Hyper-IgM syndrome with AID or UNG deficiency
• mutation in AID (activation-dependent induced cytidine deaminase) or UNG (uracil Nglycosylase) gene results in failure of class switch recombination (CSR)
• autosomal recessive inheritance
• similar presentations to X-linked agammaglobinaemia but with lymphoid hyperplasia
and no leukopaenia
• IgM is normal or increased but IgG, IgA and IgE are low
• Hyper-IgM syndrome as part of X-linked recessive ectodermal dysplasia
(XL-EDA-ID) syndrome which affects skin, sweat gland, hair, nails, teeth
and mucous membrane
• arise from mutations in NEMO (or IKKγ) gene that activate NF-kB protein, which
regulate expression of many genes including those for B cell proliferation,
differentiation into long-live plasma cells, CSR and SHM
2. Cellular immune system deficiency disorders
i. Chronic mucocutaneous candidiasis
• CMC is an autosomal dominant (AD) or autosomal recessive (AR) disorder
• Genetic defect is mutation in STAT1 (AD) and AIRE (AR) genes
• affects T cell maturation and signal transduction functions in T-cell activation
resulting in T-cell dysfunctions
• Clinical manifestations:
• persistent or recurring Candida infection of the mouth, scalp, skin, nails, eyelids,
digestive tract and vagina
• usually, this disorder is chronic, but it does not affect life span
• autoimmune poly-endocrine syndrome-hypoparathyroidism, adrenal insufficiency
• Diagnosis
• Examination of sample from infected area under the microscope to identify yeast
can confirm that a Candida infection is the cause
• Treatment
• antifungal drug such as fluconazole can be applied to the skin
ii. DiGeorge syndrome (DGS)
• DGS is an autosomal disorder with deletion of the
chromosomal regions 22q11.2 and 10p13 and the genes
in these regions esp TBX1 (T-box transcriptional factor-1)
•
•
•
•
congenital absence or underdeveloped thymus gland at birth
failure of T- cell maturation
males and females are equally affected
associated factors causing the genetic disorder are unknown
• Clinical manifestations:
• congenital heart defect (aortic arch)
• underdeveloped or no parathyroid glands (which help
regulate calcium levels in the blood). As a result, calcium
levels are low, leading to muscle spasms (tetany) within 48
hours after birth.
• Face: unusual facial features, with low-set ears, and wideset eyes, cleft palate.
• Developmental delay and learning difficulty
• Thymus gland: missing or underdeveloped leads to low
number of T cells, limiting their ability to fight many
infections – recurrent infections.
• Diagnosis
• Blood test analysis to determine;
• total number of blood cells and the number of T and B cells
• T cells and parathyroid gland functioning
• body response to vaccines by measuring immunoglobulin levels post-vaccine
challenge
• Chest x-ray may be taken to check the size of the thymus gland
• ECG and ECHO for heart defects
• Chromosomal (karyotyping) and mutagenesis study to check for abnormalities
• Treatment
• For children who have some T cells, the immune system may function
adequately without treatment. Calcium and vitamin D supplements may be
given orally to prevent muscle spasms.
• For children who have no T cells, the disorder is fatal unless transplantation of
thymus tissue or stem cell transplantation is done.
• Sometimes the heart disease is worse than the immunodeficiency, and
surgery may be needed to prevent severe heart failure or death
iii. X-linked lymphoproliferative syndrome (XLPS)
• XLPS is inherited as an X-linked recessive disorder
resulting from mutation in one or more genes
(SH2D1A/SAP and XIAP) located on the X (sex)
chromosome, affecting only males
• SH2D1A encodes signaling lymphocyte activation
molecule (SLAM) associated protein (SAP) while XIAP
encodes XIAP protein that inhibits apoptosis
enzymes (caspases 3, 7 & 9) to prevent the cell
from self-destroying itself
• Mutations in these genes result in abnormality of
T-lymphocytes and NK cells resulting in defective
response to Epstein-Barr virus (EBV) infection
*Haemophagocytic lymphohistiocytosis (HLH); *Re-stimulation induced cell death (RICD)
• Clinical manifestations:
• usually presents with no symptoms until there is EBV infection resulting in
fulminant infectious mononucleosis with liver failure
• there may be lymphoma, aplastic anaemia, another immunodeficiency
disorder, and an enlarged spleen
• about 75% of people die by age 10, and all die by age 40 unless stem cell
transplantation is done
• Diagnosis
• flow cytometry analysis of proteins on the surface of white blood cells for
abnormalities in immune cells.
• prenatal genetic screening is recommended (if any family history is present)
• Treatment
• Stem cell transplantation can cure XLPS if it is done before EBV infection or
other disorders become too severe
• Rituximab (mAb that modifies the immune system) can help prevent severe
EBV infection before transplantation is done
iv. Zeta-associated protein kinase 70 (ZAP-70) deficiency
• ZAP-70 deficiency is inherited as an autosomal recessive
disorder that occur from mutations in the ZAP-70 gene
located on chr2q11.2
• The gene encodes zeta-chain-associated protein kinase
(involved in development and functions of CD8+ and
activation of CD4+ T lymphocytes)
• Individual with this defect presents commonly with
opportunistic infections due to lack of CD8+ T cells and
abnormal CD4+ T cells
3. Combined humoral and cellular immune system deficiency disorders
i. Severe combined immunodeficiency (SCID)
• SCID is a serious, potentially fatal immunodeficiency disorder caused by
mutations in many different genes.
• All SCID forms are hereditary and congenital
• X-linked SCID
• is the most common form and results from a mutation in a gene (IL2RG) on
the X (sex) chromosome and occurs almost exclusively in boys.
• cause defect in IL-2 receptor gamma-chain also shared by IL-4, IL-7, IL-11 and
IL-15, all involved in lymphocyte proliferation and/or differentiation
• No or low levels of T cells, also cause low levels of antibodies without the help
of T cells for B cell activation and differentiation
• Natural killer cells also do not function normally
• Autosomal SCID
• arise from mutations in several genes such as recombination-activating genes
RAG-1 & RAG-2 (involved in VDJ recombination in B & T cells), Janus kinase
(JAK) & protein tyrosine phosphatase receptor type C (PTPRC)
• could also arise from mutations in adenosine deaminase (ADA) or purine
nucleoside phosphorylase (PNP) genes, resulting in accumulation of dATP or
dGTP with toxicity to lymphoid stem cells
• Clinical manifestations
• most develop pneumonia, persistent viral infections, thrush.
• all infants with this disorder have a severely underdeveloped thymus gland.
• if not treated, these children usually die before age 1 year.
• Diagnosis
• measure blood levels of and functioning of B and T cells
• screening all newborns for T-cell receptor excision circle (TREC) test
• genetic tests to identify specific mutations and to determine severity of defects
• Treatment
• nurse patients in protected environment to prevent exposure to possible
infections (reverse isolation)
• supportive treatment with antibiotics and immune globulin to prevent infections
• only effective treatment is stem cell transplantation (for example, from an
unaffected sibling with the same tissue type). If transplantation is done by age 3
months, 96% of infants survive.
• gene therapy may be effective, depending on which form of severe combined
immunodeficiency is present
ii. Ataxia telangiectasis
• AT is an autosomal recessive hereditary disorder with mutation in
ATM (ataxia telangiectasis mutated) or ATM serine/threonine
kinase gene located on chr11q22.3
• ATM proteins are involved in DNA repair especially in cells of the
nervous and immune systems
• Mutation affects normal development and function of B and Tcells often leading to low levels of immunoglobulins—IgA and
IgE—IgA is considerably reduced (in 70% of the cases)
• Clinical manifestations:
• characterized by incoordination (abnormalities in the cerebellum result in loss of
coordination), dilated capillaries, and an immunodeficiency state
• between the ages of 1 and 6 years, capillaries in the skin and eyes become dilated
and visible
• intellectual disability may develop and progress
• endocrine abnormalities (gonadal dysgenesis, testicular atrophy, infertility, DM)
• sinus and lung infections
• increase risks of cancer especially leukemia, lymphoma, brain tumors and gastric
cancer
• AT usually progresses to paralysis, dementia and death typically by age 30
• Diagnosis
• measure serum levels of IgA
• genetic testing may help confirm the diagnosis
• Treatment
• prevent infections by antibiotic prophylaxis and treat by giving immune globulins
• these therapy do not alleviate other AT problems
iii. Wiskott-Aldrich syndrome (WAS)
• WAS
• is an X-linked recessive inherited disorder (usually affects only boys) resulting
from mutation in a gene (WASP) that encodes a WASP usually expressed by
haemopoietic cells, and which function as signal transducer from receptors to
actin cytoskeleton, and are important for normal T and B cells function.
• characterized by abnormal immunoglobulin production, T- cell malfunction,
low platelet count, and eczema
• platelets are small and malformed, and are removed and destroyed by the
spleen causing thrombocytopaenia
• Clinical manifestations:
• bleeding problems due to thrombocytopaenia, usually bloody diarrhea, may
be the first symptom
• susceptibility to viral and bacterial infections, particularly of the RTI is
increased.
• risk of developing cancers (such as lymphoma and leukemia) and autoimmune
disorders (such as haemolytic anemia, inflammatory bowel disease, and
vasculitis) is increased.
• life expectancy is shortened
• Diagnosis
• complete blood count including platelets
• measure serum levels of immunoglobulins
• measure quantity and type of antibodies response to vaccines or antigen
challenge
• genetic testing may be done to identify the mutation and confirm the
diagnosis
• Treatment
• stem cell transplantation is necessary to preserve life. Without it, most will die
by age 15 years
• antibiotics are given continuously to prevent infections, and immune globulin
is given to provide the missing antibodies.
• antiviral drug (acyclovir) is given to prevent viral infections,
• platelet transfusions to relieve bleeding problems
iv. Hyper-IgE syndrome (HIES)
• HIES (Job syndrome) is an autosomal dominant (AD) or autosomal recessive (AR)
inherited disorder that results in very high levels of immunoglobulin E (IgE)
• Genetics of HIES
• HIES-AD occurs with mutation in signal transduction and activator of transcription-3 (STAT3) gene.
STAT3 protein is a signal transducer for maturation of B and T lymphocytes
• HIES-AR occurs with mutations in tyrosine kinase 2 (TYK2) or dedicator of cytokinesis (DOCK8)
genes. TYK2 protein is a member of the Janus kinases (JAK) protein families involved in cytokine and
type 1 IFN signaling. DOCK8 protein act as guanine nucleotide exchange factor (GEF) which activate
GTPases involved in chemical signaling necessary for proper functions of B, T and NK cells
• Clinical manifestations:
• in most infants, recurrent abscesses form in the skin, joints, lungs, or other
organs caused by staphylococcal species
• rashes may occur
• bones are weak, resulting in many fractures.
• facial features may be coarse, and loss of baby teeth is delayed.
• life span depends on the severity of the lung infections
• Diagnosis
• measure serum levels of IgE
• genetic tests can be done to check for the abnormal genes
• Treatment
• antibiotics, usually trimethoprim/sulfamethoxazole, are given continuously to
prevent staphylococcal infections.
• rash is treated with moisturizing creams and antihistamines.
• certain drugs that modify the immune system, such as interferon gamma, are
sometimes helpful
v. Combined immunodeficiency with inadequate (but not absent)
T-cell functions and normal or elevated immunoglobulins
• This is an autosomal recessive or X-linked inherited disorder resulting from
mutations in NEMO (nuclear factor kappa-B essential modulator) gene also
known as IKBKG (inhibitor of nuclear factor kappa-B kinase subunit gamma)
gene.
• IKBKG or NEMO encodes IKBKG or NEMO (IKKγ), the regulatory subunit of IKK (IkB
kinase) protein complex (IKKα-IKKβ-NEMO), which modulates NFK-β, enabling it to
bind DNA to regulate expression of other genes including those of the immune
system and inflammation. Mutations result in defects in T and B cell functions
• Clinical manifestations:
•
•
•
•
•
common and opportunistic infections
lymphopaenia
lymphadenopathy
hepatosplenomegaly
skin lesions resembling those of Langerhans cell histiocytosis in some patients
vi. MHC antigen deficiencies
• Autosomal recessive inherited disorders involving
mutations in several genes including Regulatory Factor
X (RFX) genes such as RFX5 (chr1q21.3), RFXAP (RFXassociated protein) (chr13q13.3), and RFXANK (RFX
containing ankyrin repeats) (chr19p13.11)
• These genes encode Regulatory Factor X (RFX) family
of transcription factors essential for MHC class II gene
expression through a DNA sequence motif called Xbox
• Mutations in the RFX genes results in bare
lymphocyte syndrome (BLS) with combined deficiency
of B and T lymphocytes
• This condition presents as common and opportunistic
infections
vii. Cartilage hair hypoplasia
• Autosomal recessive inherited disorder with mutations (>100) of the
ribonuclease mitochondrial RNA processing (RMRP) gene (90% of
cases has 70 A>G)
• Normal RMRP gene (chr9p13.3) produces a non-coding RNA (not a
mRNA), which binds many proteins to form an enzyme called
mitochondrial RNA-processing endoribonuclease or RNAse MRP. This
enzyme is important in mitochondrial DNA synthesis, ribosomal RNA
processing (for protein translation) and control cell cycles in cells
including immune system.
• Clinical manifestations of CHH;
•
•
•
•
•
short limb dwarfism
skeletal abnormalities
sparse hair growth (hypotrichosis)
common and opportunistic infections
elevated cancer risks
(B) Primary innate immune deficiency disorders
• The inherited primary genetic disorders of the cells of the innate
immune system include;
• Phagocyte disorders
• Complement disorders involves:
•
•
•
•
complement proteins (C1-C9)
complement pathways
regulatory proteins
complement receptors
• Toll-like receptors polymorphism & TLR pathways deficiency
1. Phagocyte deficiency disorders
i. Chediak-Higashi syndrome (CHS)
• CHS is a very rare autosomal recessive hereditary disorder with mutations
(>30) in the LYSosomal Transporter (LYST) or CHS1 gene. This results in
LYSosomal Trafficking (LYST) defects
• LYST or CHS1 gene (chr1q42.3) encodes a protein called lysosomal
trafficking regulator, which regulates transport (trafficking) of materials to
the lysosomes (recycling centers for the cell). Mutations lead to abnormal
lysosomes, which interferes with cell function including phagocytes and
melanocytes.
• Clinical manifestations:
little or none of the pigment melanin is formed (albinism)
may also cause vision problems (acuity, photosensitivity, nystagmus)
infections of the respiratory tract, skin, and membranes lining the mouth.
in about 80% of cases, there is fever, jaundice, hepatosplenomegaly,
lymphadenopathy, and tendency to bleed and bruise easily
• can also affect the nervous system
• respiratory burst is normal
• once symptoms develop, the syndrome is usually fatal within 30 months
•
•
•
•
• Diagnosis
• genetic testing
• complete blood count
• Treatment
• antibiotics to help prevent infections
and interferon gamma to help the
immune system function better.
• corticosteroids and removal of the
spleen (splenectomy) sometimes
temporarily relieve symptoms.
• however, unless stem cell
transplantation is done, most
people die of infections by the time
they are 7 years old. About 60% of
children are alive 5 years after
transplantation.
ii. Chronic granulomatous disease (CGD)
• CGD can be inherited as an X-linked recessive disorder (occurring only in boys) and
sometimes as an autosomal recessive disorder
• Genetics of CGD
• X-linked CGD results from mutations (>650) in cytochrome b-245-beta polypeptide chain (CYBB) gene
(Xp21.1-p11.4) which encodes cytochrome b-245 beta chain (gp91phox) of NADPH oxidase complex
responsible for phagocyte destruction of foreign antigens
• AR CGD results from;
• mutations (>40) in cytochrome b-245-alpha polypeptide chain (CYBA) gene (chr16q24.2) which encodes cytochrome
b-245 alpha chain (p22phox)
• mutations (95% of cases have 75-76delGT) in neutrophil cytosolic factor-1 (NCF-1) gene (chr7q11.23) which encodes
neutrophil cytosolic factor (p47phox) and mutations (>50) in neutrophil cytosolic factor-2 (NCF-2) gene (chr1q25.3)
which encodes neutrophil cytosolic factor (p67phox)
• In CGD, phagocytes can ingest microbes but cannot produce reactive oxygen species
(such as hydrogen peroxide and superoxide) necessary to kill certain bacteria and fungi
• Clinical manifestations:
• chronic infections occur in the skin, lungs, lymph nodes, mouth, nose, urinary tract, and intestines.
Abscesses can develop around the anus and in the lungs and liver
• children may grow slowly
• Diagnosis
• measures blood activity of phagocytes in
response to microorganisms.
• genetic tests- to check for the specific mutations
that cause this disorder
• Treatment
• antibiotics, usually trimethoprim/
sulfamethoxazole, are given regularly and
indefinitely to prevent infection.
• antifungal drugs (such as itraconazole) are
usually also given regularly to help prevent fungal
infections
• interferon gamma (a drug that modifies the
immune system), injected 3 times a week, can
reduce the number and severity of infections.
• transfusions of granulocytes can be lifesaving.
• stem cell transplantation has cured some people
with CGD
iii. Leukocyte adhesion deficiency (LAD)
• LAD is inherited as an autosomal recessive disorder of
leukocytes
• Genetics of LAD
• Type I LAD results from mutations (>90) in integrin β-2 (ITG β-2) gene
(chr21q22.3) which encodes the CD18 of β-2 integrins (CD11b/CD18
or CR3) required for leukocyte adhesion to blood vessels and
transport across them to area of injury
• Type II LAD (congenital disorder of glycosylation 2C) results from
mutations in the soluble carrier family 35 member C1 (SLC35C1)
gene (chr11p11.2), which encodes a GDP-fucose transporter found
in Golgi apparatus involved in import of GDP-fucose from cytoplasm
to the Golgi body for protein glycosylation
• These mutations make the leukocytes less able to travel to
sites of infection and to kill and ingest bacteria and other
foreign invaders.
• Clinical manifestations:
• in severely affected infants, infections develop in soft tissues, such as the
gums, skin, and muscles. No pus forms in infected areas. Infections become
increasingly difficult to control.
• wounds do not heal well.
• often, the umbilical cord is slow to fall off, taking 3 weeks or
• more after birth.[ Normally, it falls off in 1 or 2 weeks after birth]
• most children with severe disease die by age 5
• Diagnosis
• complete blood count
• flow cytometry to measure proteins on the surface of white blood cells
• Treatment
•
•
•
•
antibiotics given continuously, to prevent infections.
transfusions of granulocytes (a type of white blood cells) can also help.
stem cell transplantation is the only effective treatment that may provide cure
gene therapy for this disorder is being studied
iv. Cyclic neutropaenia (CN)
• CN and severe congenital neutropaenia (SCN) is an autosomal dominant
inherited disorder of neutrophils resulting from mutations in the elastase
2 (ELA-2) gene
• ELA2 gene encodes neutrophil elastase, a serine proteinase, which
hydrolyses elastin, collagen-IV and many other proteins of microbial
pathogens within lysosomal granule called “azurophil” granules but can
also hydrolyze human cellular proteins if released outside the granules.
• Mutations in ELA2 causes failure of neutrophils to mature resulting in CN
and SCN
• Clinical manifestations
• marked by low numbers of circulating neutrophil.
• neutropenia lasts about a week during which the patients are susceptible to
infection.
v. Mendelian susceptibility to mycobacterial disease (MSMD)
• MSMD, also known as familial disseminated atypical mycobacterial
infection, is an inherited autosomal dominant or autosomal recessive
disorder of interferon-gamma receptor-1 & 2 (IFN-γR -1 & 2), IL-12 and
IL-12R genes.
• Genetics of MSMD
• IFN-γR-1 gene (chr6q23.3) encodes ligand binding alpha chain of gamma
interferon important for T-cell activation
• IL-12A (chr3p12-q13.2) encodes a 35kD IL-12 subunit while IL-12B (chr5q33.3)
encodes a 40 kD cytokine receptor-like subunit. IL-12 is a disulphide-linked
heterodimer of these 2 subunits produced by dendritic cells, macrophages,
neutrophils and human B-lymphoblastoid cells, and involved in T-cell growth,
differentiation (Th1) and activation to produce IFN-gamma & TNF-alpha
• IL-12RB1 gene (chr19p13.11) encodes type I transmembrane protein and IL12RB2 gene (chr1p31.3) encodes also a type I transmembrane protein. Coexpression of both proteins leads to formation of high-affinity receptor binding
for IL-12
• Mutations in any of these genes results in defective leukocyte as well
as T cell functions
• Clinical manifestations
• Mycobacterial infections usually caused by atypical mycobacteria or MOTT
• Different degree of severity depending on the defects
2. Complement deficiency disorders
• Four aspects of primary complement deficiency disorders:
•
•
•
•
Complement
Complement
Complement
Complement
proteins (C1-C9)
pathways – (Classical, MBL/MASPs and alternate pathways)
regulatory proteins
receptors
• These disorders are inherited as autosomal recessive or X-linked (in
properdin deficiency) from mutations affecting the genes encoding
the complement proteins, pathway proteins, regulatory proteins
and complement receptors
• *Mannose-associated serine proteases
i. Complement proteins and complement pathway deficiencies
• Classical pathway genes
• C1complex - [C1qA & C1qB (chr1p36.3-34.1),
C1qC (chr1p36.12)], C1r (chr12p13.31), C1s
(chr12p13.31)
• C2 (chr6p21.33)
• C4 (chr6p21.3)
• Alternate pathway genes
•
•
•
•
Factor D (chr19p13.3)
Factor B (chr6p21.3)
Properdin (Xp11.3-11.23)
C3 (chr19p13.3-13.2)
• MBL/MASPs pathway genes
•
•
•
•
MASP (chr3q27.3)
MBL (chr10q21.1)
C2 (chr6p21.33)
C4 (chr6p21.3)
• Terminal pathways
• C4 (chr6p21.3), C5 (chr9q34.1), C6 (chr5p13.1),
C7 (chr5p13.1), C8 (A & B chr1p36.2-22.1; G
chr9q34.3), C9 (chr5p13.1)
ii. Complement regulatory proteins and receptor deficiencies
• C1 inhibitor deficiency causing hereditary angioedema
• an autosomal dominant inherited disorder
• results from mutations (>250) in the serping 1 gene (chr11q12.1) which normally
encodes C1 inhibitor, a serine protease inhibitor (serpin), which blocks the
activity of many plasma proteins including kallikrein and activated factor XII
(factor XIIa), thereby blocking bradykinin release and reducing inflammation.
• uncontrolled inflammation leads to angioedema
• Factor H and Factor I deficiencies
• are inherited as autosomal co-dominant disorders resulting from mutations in
CFH gene (chr1q31.3) and CFI gene (chr4q25)
• present as C3 deficiency but factor H deficiency may be associated with HUS
• Decay acceleration factor deficiency
• an autosomal recessive inherited disorder resulting from mutation in the DAF or
CD55 gene (chr1q32.2) which encodes DAF or CD 55 molecule that recognizes
C4b and C3b and inhibit complement activation
• mutational deficiency is associated with paroxysmal nocturnal haemoglobinuria
• CR3 deficiency
• autosomal recessive inherited disorder from mutations in the ITGβ-2 gene
(chr21q22.3), which encodes CR3 (CD11b/CD18 or β-2 integrins) and results
in leukocyte adhesion deficiency
• CR1 deficiency*
• acquired disorder which occurred as secondary finding in immune-complex
mediated disease
3. Toll-like receptor & pathways deficiency disorders
Toll-like receptors
Toll-like receptor signaling pathways
• MyD88-dependent pathway (all TLRs except TLR3)
• MyD88-IRAK (IL-1 receptor associated kinase) complex (Myddosome) interacts
with Mal/TIRAP (TIR domain-containing adapter protein) in TLR 1/2/4/5/6 for
signaling, leading to activation of NF-kβ which control expression of genes for
proinflammatory cytokines
• MyD88-Mal/TIRAP interactions in TLR 7/8/9 for signaling, leading to NF-kβ
activation and proinflammatory cytokines expression
• TRIF (TIR-domain containing adapter-inducing interferon-β)dependent pathway (for TLR3 and TLR4)
• TRIF interacts with TRAM (TRIF-related adaptor molecule) for signaling in TLR4,
leading to activation of transcription factor, IR3, which control expression of
type 1 interferons
• TRIF is used as sole adaptor for signaling in TLR3, with activation of
transcription factor, IR3, which control expression of type 1 interferons
• There may also be TLR3-Unc93b-TRIF-TRAF (tumor necrosis factor receptor
associated factor) signaling in TLR3 leading to activation of NF-Kβ & MAPK which
regulate B-cell survival.
• *SARM adaptor that inhibit TRIF pathway (negative feedback) pathway for
TLR3/TLR4
Primary immunodeficiency of TLRs
• These are very rate diseases in the general population but complete
defects in two main TLR-dependent pathways have been described so
far.
• MyD88-IRAK4 deficiency
• homozygous or compound heterozygous mutations in IRAK4 (chr12q12) (n=20) or
MYD88 (chr3p22.2) (n=4) genes that abolish IRAK4 & My88D proteins production
• leads to greater susceptibility to pyogenic bacteria infection
• TLR3-Unc93b-TRAF3 deficiency
• may be autosomal dominant or recessive inherited disorder from mutations in TLR3
(chr4q35.1) OR autosomal dominant mutation of TRAF3 (chr14q32.32) or autosomal
recessive mutations in Unc93B1 (chr11q13.2) (which encodes a molecule in the TLR3
pathway) or autosomal recessive or dominant mutation of TRIF (chr19p13.3) genes.
• All these mutations lead to greater susceptibility to herpesvirus infections (reason
remained a mystery)
SECONDARY IMMUNODEFICIENCIES
• These are acquired immunodeficiency disorders occurring in an host with
intrinsically normal immune system
• They are caused by extrinsic factors including genetic (not primarily of the
immune system) and metabolic multisystemic syndromes
• They are more commonly encountered in routine clinical practice than
primary immunodeficiencies
• Usually do not manifest at birth and are heterogenous in their clinical
presentations in older age groups depending on the magnitude of the
external factors and host susceptibility
• Causes of secondary immunodeficiencies
• physiological and immunocompromising diseases
• immunosuppressive drug therapy (anti-inflammatory, immunomodulatory and
immunosuppressive)
Extrinsic factors of secondary immunodeficiencies
1. Physiological and immunocompromising diseases
i. Physiological
• Neonates
• prematurity (fewer maternal Igs),
• relatively immatured secondary lymphoid organs
• immatured innate immune cells (decreased neutrophils, TLR signaling, cytokines
and complements)
• Advanced age (elderly)
• development of oligoclonality (expansion of oligoclonal CD8+ T cells usually
beginning around 70 years of age) with limited capacity of thymus to generate
naïve T cells
• restricted B-cell diversity repertoire with limited response to vaccines
• compromised innate immune system such as skin and mucous membranes from
endocrinological and metabolic effects of aging
• may combine with other external factors such as malnutrition, chronic diseases
etc
ii. Malnutrition
• PEM is the most common cause of immunodeficiency
worldwide occurring from lack of access to food
sources, chronic diseases that induce cachexia such
as neoplastic diseases, alcoholism
• Hypoproteinaemia leads to proportionate decrease
in;
• T cell production and function
• humoral immune responses to vaccines
• Micronutrients deficiency;
• zinc and vitamin C deficiency increase susceptibility to
infections through weakening of barriers which
increase invasion by pathogens
• vitamin D deficiency leads to defects in macrophage
activity for killing of intracellular pathogens especially
M. tuberculosis
iii. Metabolic diseases
• Two important metabolic diseases associated with secondary immunodeficiencies
are DM and uraemia
• DM – chronic hyperglycaemia can lead to;
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defective phagocytic functions and macrophage chemotaxis (in vitro)
T-cell anergy (delayed hypersensitivity skin reaction)
poor lymphoproliferative response to mitogens
complications of vasculopathy and neuropathy leads to frequent microbial infections
• Uraemia
• chronic activation of immune system lead to immune hyporesponsiveness
• decreased capacity to generate memory B cell response to vaccines
• defective phagocyte chemotaxis and microbicidal activity (in vitro)
iv. Inherited diseases other than primary immunodeficiencies
• Inherited diseases with genetic defects that does not affect the immune
system but individuals with such defects may present with
immunodeficiency state (mechanism of this is not fully understood)
• These genetic defects are mostly chromosomal number abnormalities e.g.
• Down syndrome (Trisomy 21)
• abnormalities of B and T cells (number and function)
• defective neutrophil chemotaxis and phagocytosis (in vitro) due to overexpression
of a gene, Down syndrome critical region 1 (DSCR1)
• Turner syndrome (45XO)
• hypogammaglobinaemia (cause unknown, no gene identified)
• Cystic fibrosis (CF)
• mutations in cystic fibrosis transmembrane conductance regulator gene
• defective innate immune mechanism of the airways with inability to clear mucous
secretions, which predisposes the individuals to frequent Pseudomonas infections
v. Infectious diseases
• Transient immunosuppression by viruses have been reported since the 1900s when
tuberculin skin test was negative in patients in acute phase of measles. Measles,
Mumps, CMV, influenza virus etc can all cause transient and less severe
immunosuppression
• Mechanism of immunosuppression by microorganisms;
• microbial agents or their toxins or metabolites in large amount can activate the immune
system to a non-responsive state such as T-cell anergy or functional exhaustion e.g. TB,
HIV, staphylococcal TSS
• tissue destruction by microbial-induced damage or inflammatory reactions may give
access to other microbial pathogens to cause secondary infections
• infection of bone marrow by bacteria and viral agents to cause neutropaenia or
pancytopaenia especially in immunocompromised persons e.g. parvovirus B19,
Salmonella typhi
• HIV causes severe and permanent immunosuppression by causing T-cell
lymphopaenia through such mechanisms as;
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•
specific HIV-induced apoptosis and apoptosis caused by nonspecific immune activation
viral cytopathic effect
cytotoxicity to HIV-infected cells
cell death by autophagy in which organelles are sequestered and directed toward
lysosomal pathways induced by HIV env protein in uninfected T cells
vi. Other diseases
• Haematological disorders
• aplastic anaemia
• sickle cell disease (from auto-splenectomy)
• GvHD
• Neoplastic disorders
• Hodgkin's lymphoma
• haematological malignancies (such as CLL, MM)
• Gastrointestinal disorders
• hepatic insufficiencies
• protein loosing enteropathy
• intestinal lymphangiectasia
• Rheumatologic disorders
• SLE
• Chronic illnesses
• sarcoidosis
• histiocytosis
vi. Surgery and trauma
• Surgery and trauma (including burns) cause disruption of epithelial barriers and
cell injury that triggers inflammatory reaction to promote healing and local
microbicidal activity
• Massive tissue injury from trauma and surgery can lead to;
• acute phase inflammatory reactions involving TLR signaling with release of
proinflammatory cytokines (IL-6, TNF-alpha) and adaptive immune response.
• In the lungs, this may lead to adult respiratory distress syndrome (ARDS) or multiorgan systemic inflammatory response syndrome (SIRS)
• Surgical splenectomy;
• patients are susceptible to infections by encapsulated bacteria such S. pneumoniae, H.
influenzae and N. meningitidis
• mortality in such patients is 50-70% hence the need to avoid splenectomy as much as
possible
vii. Environmental factors
• These include; UV light, ionizing radiation, high altitude/extreme cold/chronic
hypoxia and space flights
• UV light (sunlight)
• induces T-cell apoptosis
• non-specific release of tolerogenic cytokines from APC in the skin
• differentiation of regulatory T cells
• Ionizing radiation
• depletes bone marrow cell lineages (all) – cytopaenias (although humoral and
phagocytes are relatively radio-resistant)
• space radiation – weakness of T-cell immune response and reactivation of latent viral
infection
• Chronic hypoxia/high altitude and long duration space flights (immobility)
• physical and mental stress affects corticoadrenal regulation with release of cortisol
• increased level of pro-inflammatory cytokines (IL-6, TNF-alpha) and suppression of
anti-inflammatory cytokines (IL-10)
2. Immunosuppressive drug therapy
• These include anti-inflammatory, immunomodulatory and immunosuppressive
drugs which are used to ameliorate undesirable immune responses
• They are commonly used in clinical practice for inflammatory conditions such as
autoimmune disorders, allergic disorders, transplant rejection, and graft-versushost disease (GvHD)
• Immunosuppressive therapy can be categorized as;
• physical agents e.g. UV light and ionizing radiation
• chemical agents – most available in clinical practice with common ability to inhibit
lymphocyte proliferation but lack specificity for the immune response causing the
illness
• biological agents – developed to increase immune specificity by targeting specific
components of the immune system
• Other drugs with immunosuppressive effects unrelated to their biologic action e.g.
anti-epileptic drugs (hypogammaglobinaemia), trimethoprim-sulfamethoxazole
(leukopaenia)
• Immunosuppressive drugs
• Corticosteroids
• only glucocorticoids (and not mineralocorticoids)
have significant anti-inflammatory activity
• GC acts by inhibiting expression of inflammatory
cytokines (IL-1, IL-6, TNF-alpha) through nuclear NFkβ activation, inhibit leukocyte chemotaxis, cell
adhesion, phagocytosis and lymphocyte anergy
• in large amount, both humoral and cellular immune
responses are impaired, predisposing individuals to
infection by microorganisms
• Calcineurin inhibitors
• inhibitors bind to cytoplasmic protein from
immunophilin family and inhibit their interactions
with calcineurin, which is essential for IL-2
transcription and T-cell function (spares
macrophages and neutrophils)
• used in GvHD, organ transplant and corticosteroidR ADs. e.g. cyclosporine, tacrolimus, pimecrolimus
• associated with severe lymphoproliferative
disorders and skin neoplasia and less severe cases
of hypertension and renal dysfunctions
• Cytotoxic drugs
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act as anti-neoplastic and bone marrow ablation prior to transplantation
immunosuppressive for inflammatory diseases, autoimmune disorders, GvHD etc
interferes with DNA synthesis, cell cycle arrest and inducing apoptosis
inhibit both B and T cell proliferation therefore any new immune responses
toxicity to haematopoeitic (cytopaenias – secondary immunodeficiency) and nonhaematopoeitic cells (skin, GIT)
• Disease modifying anti-rheumatic drugs (DMARDs)
• anti-cytokine inhibitors e.g. IL-1 inhibitors (anakinra), IL-6 inhibitors (tocilizumab), IL-17
inhibitors (brodalumab), TNF-alpha inhibitors (adalimumab, etanercept, infliximab)
• T-cell activation inhibitors e.g. abatacept, basiliximab
• CD20 inhibitors e.g. rituximab
• CD3 inhibitors e.g. muromonab-CD3
• Janus kinase (JAK) inhibitors e.g. ruxolitinib
• Immunosuppressive immunoglobulins
• anti-lymphocyte and anti-thymocyte globulins
• Other immunosuppressive drugs
• anti-convulsant drugs e.g. phenytoin, sodium valproate, lamotrigine
• purine metabolism inhibitors e.g. azathioprine, mycophenolate mofetil
• rapamycins (macrolide immunosuppressants) e.g. everolimus, sirolimus
GENERAL APPROACH TO DIAGNOSIS AND MANAGEMENT
OF IMMUNODEFICIENCY DISORDERS
• Presenting complaints
• frequent infections – mucosal surfaces by bacterial and fungal agents manifesting as fever,
abdominal pain/discomfort (hepatosplenomegaly),
• chronic diarrhoea,
• failure to thrive (FTT)
• other symptoms will depend on type and severity of the disorders
• History
• infections
• multiple infections in many anatomic sites, increasing frequency and severity of infections with age,
recurrent serious infections with common pathogens, serious infections with unusual pathogens
• positive family history of immunodeficiency disorders
• age
• < 6 months of age – abnormality in T cells
• 6-12 months of age – abnormality of both B and T cells or B cells
• > 12 months of age – abnormalities of B cells and antibody production
• underlying risk factors:
• DM, drugs, nutrition, IVD, transfusion history (HIV)
• Laboratory investigations
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CBC – total and differentials
serum immunoglobulins estimation (baseline and after vaccine challenge)
skin test e.g. tuberculin skin test for cellular immunity against TB
lymph node biopsy for histopathological examinations
genetic testing
• Screening by blood test for genetic abnormality (prenatal testing after parent counselling)
• Screening all newborn in some country for genetic abnormalities of T cells (T cell receptor excision circle TREC test)
• Treatment
general measures and certain vaccines to prevent infection
antibiotics and antiviral when needed
immune globulin sometimes
stem cell transplantation (from bone marrow, blood including cord blood, thymus) is definitive but
usually reserved for severe disorders
• gene therapy (along SCT) provides potential cure
• treat underlying conditions in secondary immunodeficiency disorders
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• Prevention (depends on type of disorders)
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periodic immune globulin treatment will prevent infection
good personal and dentine hygiene
avoid eating undercooked food
avoid drinking contaminated water
avoid contact with people who have infections
• End of Lecture
•Q&A