PRIMARY IMMUNE

DEFICIENCY DISEASES,
AUTOIMMUNITY and
AUTOIMMUNE DISEASES
HUMAN IMMUNE SYSTEM:
• Divided into 2 major components:

• A. INNATE IMMUNE SYSTEM

• Provides the rapid triggering of inflammatory responses based
on the recognition (at the cell surface or within cells) of:
• 1. molecules expressed by microorganisms
• 2. molecules that serve as “danger signals” released by cells under
attack
• Myeloid cells (i.e., neutrophils and macrophages) play a major
role because of their phagocytic capacity

• B. ADAPTIVE IMMUNE SYSTEM:

• Operates by clonal recognition of antigens followed by a
dramatic expansion of antigen-reactive cells and execution of
an immune effector program
• Effector cells die off rapidly whereas memory cells persist
• B lymphocytes are dependent on T lymphocytes in generating
long-lived humoral immunity
PRIMARY IMMUNODEFICIENCY
(PID):
• PIDs are genetic diseases with primarily Mendelian
inheritance

• Overall prevalence: 5 per 100,000 individuals

• Can involve all possible aspects of immune responses (innate,

adaptive, cell differentiation, and effector function and
regulation)

• PIDs are classified according to:

• 1) the arm of the immune system that is defective
• 2) the mechanism of the defect (when known)
CLASSIFICATION of PRIMARY
IMMUNE DEFICIENCY DISEASES:
• I. DEFICIENCIES of the INNATE IMMUNE SYSTEM

A. PHAGOCYTIC CELLS
• 1. Impaired production: Severe Congenital Neutropenia (SCN)
• 2. Asplenia
• 3. Impaired adhesion: Leukocyte Adhesion Deficiency (LAD)
• 4. Impaired killing: Chronic Granulomatous Disease (CGD)

B. INNATE IMMUNITY RECEPTORS and SIGNAL TRANSDUCTION

• 1. Defects in Toll-like receptor signaling
• 2. Mendelian susceptibility to mycobacterial disease (MSMD)

C. COMPLEMENT DEFICIENCIES
• 1. Classical, alternative and lectin pathways
• 2. Lytic phase
CLASSIFICATION of PRIMARY
IMMUNE DEFICIENCY DISEASES:
• II.DEFICIENCIES of the ADAPTIVE IMMUNE SYSTEM

A. T LYMPHOCYTES
• 1. Impaired development
• a. Severe combined immune deficiencies (SCIDs)
• b. DiGeorge Syndrome
• 2. Impaired survival, migration, function
• a. Combined immunodeficiencies
• b. Hyper-IgE Syndrome (autosomal dominant)
• c. DOCK8 Deficiency
• d. CD40 Ligand Deficiency
• e. Wiskott-Aldrich Syndrome
• f. Ataxia-Telangiectasia and other DNA repair deficiencies

B. B LYMPHOCYTES
• 1. Impaired development: XL and AR agammaglobulinemia
• 2. Impaired function
• a. Hyper-IgM syndrome
• b. Common Variable Immunodeficiency (CVID)
• c. IgA deficiency
CLASSIFICATION of PRIMARY
IMMUNE DEFICIENCY DISEASES:
• III. REGULATORY DEFECTS

A. INNATE IMMUNITY
• 1. Autoinflammatory syndromes
• 2. Severe Colitis

B. ADAPTIVE IMMUNITY
• 1. Hemaphagocytic lymphohistiocytosis (HLH)
• 2. Autoimmune Lymphoproliferation Syndrome (ALPS)
• 3. Autoimmunity and Inflammatory Diseases (IPEX, APECED)
DIAGNOSIS of PRIMARY
IMMUNODEFICIENCIES:
• The following should prompt the diagnosis of PID:
• Presence of recurrent or unusually severe infections
• Recurrent allergic or autoimmune manifestations

• The following medical information should be obtained:

• A detailed account of the patient’s personal history
• Family medical history up to several generations of ancestors

• Clinical examination should focus on:

• Primary symptoms
• Size of lymphoid organs
• Characteristic signs of a number of complex syndromes that may
be associated with a PID
TESTS to DIAGNOSE PID:
 PRIMARY
IMMUNODEFICIENCIES
of the
IMMUNE SYSTEM
DIFFERENTIATION of
PHAGOCYTIC CELLS and RELATED
PIDs:
I. SEVERE CONGENITAL
NEUTROPENIA (SCN)
• Characterized by severely impaired neutrophil counts ( <500 PMNLs/ µL of blood)
• Usually manifested from birth
• Autosomal dominant is the most frequent inheritance pattern

• MANIFESTATIONS:
• Bacterial infections at the interface between the body and the external milieu (e.g.,
the orifices, wounds, respiratory tract) rapidly progressing through soft tissue followed
by dissemination in the bloodstream
• Severe visceral fungal infections
• The absence of pus is a hallmark of this condition

• DIAGNOSIS:
• Requires examination of the bone marrow
• Associated with a block in granulopoiesis at the promyelocytic stage

• TREATMENT:
• Careful hygiene measures in infants
• Oral and dental care
• Prophylactic administration of trimethoprim/sulfamethoxazle to prevent bacterial
infection
• Subcutaneous injection of the cytokine granulocyte colony-stimulating factor (G-
CSF) to improve neutrophil development and thus prevents infection
II. ASPLENIA
• Primary failure of the development of a spleen may be:
• 1. syndromic (Ivemark syndrome)
• 2. isolated with an autosomal dominant expression

• MANIFESTATIONS:
• Due to the natural absence of natural filtration of microbes in the
blood, asplenia predisposes affected individuals to fulminant
infections by encapsulated bacteria, most commonly in the first
years of life

• DIAGNOSIS:
• Abdominal ultrasonography
• Detection of Howell-Jolly bodies in RBCs

• TREATMENT:
• Prophylaxis with twice-daily oral Penicillin
• Vaccination
III. GATA2 DEFICIENCY
• GATA2 (Zinc Finger Transcription Factor):
• A transcription factor involved in hematopoiesis

• A dominant mutation in GATA2 results in an immunodeficiency

with the following features:
• 1. monocytopenia
• 2. dendritic and lymphoid (B and natural killer cell) deficiency

• MANIFESTATIONS:
• Lymphedema
• Myelodysplasia
• Acute myeloid leukemia
• Life-threatening bacterial and viral infections
IV. LEUKOCYTE ADHESION
DEFICIENCY (LAD)
• DEFECT:
• Leukocytes are not able to adhere to and tansmigrate through the vascular
endothelium to reach and phagocytose their targets

• MANIFESTATIONS:
• Because neutrophils are not able to reach infected tissues, affected
individuals become susceptible to bacterial and fungal infections
• Impaired wound healing
• Delayed loss of the umbilical cord

• DIAGNOSIS:
• Suspected in cases of pus-free skin/tissue infections and massive
hyperleukocytosis (>30,000/µL), mostly granulocytes
• Immunoflourescence and functional assays to detect β2 integrin

• TREATMENT:
• HSCT (hematopoietic stem cell transplantation)
• Gene therapy
V. CHRONIC GRANULOMATOUS
DISEASES (CGDs)
• Characterized by impaired phagocytic killing of microorganisms by
neutrophils and macrophages
• Incidence: 1 per 200,000 live births
• 70% of cases are associated with X-linked recessive inheritance

• DEFECT:
• Defective production of reactive oxygen species (ROS) in the phagolysosome
membrane following phagocytosis of microorganisms

• MANIFESTATIONS:
• Recurrent skin infections due to:
• Catalase-positive bacteria (S. aureus, Serratia marcescens)
• Burkholderia cepacia
• Pathogenic mycobacteria
• Fungi (filamentous molds, Aspergillus)
• Deep-tissue bacterial and fungal abscesses in macrophage-rich organs (lymph
nodes, liver, lungs)
CHRONIC GRANULOMATOUS
DISEASES (CGDs):
• DIAGNOSIS:
• Based on assays of ROS production in neutrophils and monocytes

• TREATMENT:
• Bacterial infections- combination therapy with antibiotics that are
able to penetrate into cells
• Fungal infections- aggressive, long-term use of antifungals
• Inflammatory/granulomatous lesions- glucocorticoids
• Prophylaxis:
• Trimethroprim/sulfamethoxazole
• Azole derivatives
• Interferon γ
• HSCT
• Gene therapy
VI. MENDELIAN SUSCEPTIBILITY to
MYCOBACTERIAL DISEASE (MSMD)
• Characterized by a defect in the interleukin-12 (IL-12)-
interferon- γ (IFN-γ) axis which leads to impaired IFN-γ-
dependent macrophage activation
• Recessive and dominant modes of inheritance

• MANIFESTATIONS:
• A specific and narrow vulnerability to tuberculous and non-
tuberculous mycobacteria
• Salmonella infections

• TREATMENT:
• IFN-γ
VII. TOLL-LIKE RECEPTOR (TLR)
PATHWAY DEFICIENCIES
• Recessive mutations in genes that encode essential adaptor
molecules (IRAK4 and MYD88) involved in the signaling
pathways of Toll-like receptors (TLRs)

• MANIFESTATIONS:
• Early-onset, invasive Sterptococcus pneumoniae infections or less
frequently Staphylococcus aureus or other pyogenic infections
• Very specific susceptibility to herpes simplex encephalitis
• Mycobacterial infection
VIII. COMPLEMENT DEFICIENCY
• COMPLEMENT SYSTEM:
• Composed of a complex cascade of plasma proteins that leads to
the deposition of C3b fragments on the surface of particles and
the formation of immune complexes that can culminate in the
activation of a lytic complex at the bacterial surface

• C3 cleavage can be mediated via 3 pathways:

• 1) classic
• 2) alternate
• 3) lectin

• C3b coats particles as part of the opsonization process that

facilitates phagocytosis following binding to cognate receptors
VIII. COMPLEMENT DEFICIENCY
• CLASSIC PATHWAY:
• A deficiency in any component (C1q, C1r, C1s, C4, C2, C3, factor 1 and ficolin-3)
can predispose any individual to bacterial infections that are tissue-invasive or
that occur in the respiratory tract

• ALTERNATIVE PATHWAY:
• Deficiencies in factor D and properdin are associated with the occurrence of
invasive Nisseria infections

• LYTIC PHASE:
• Deficiencies in C5, C6, C7, C8 and to a lesser extent, C9 predispose affected
individuals to systemic infection by Nisseria

• DIAGNOSIS: Functional assays

• CH50 Test- classic pathway
• AP50 Test- alternative pathway

• TREATMENT:
• Vaccination
• Daily administration of oral Penicillin
 PRIMARY
IMMUNODEFICIENCIES
of the
ADAPTIVE IMMUNE SYSTEM
T CELL DIFFERENTIATION,
EFFECTOR PATHWAYS and
RELATED PIDs
I. T LYMPHOCYTE DEFICIENCIES
• T CELL EFFECTORS:
• 1. FOLLICULAR HELPER (TFh) CD4+ T cells
• Required for T-dependent antibody production, including the generation
of IgG class-switched, high-affinity antibodies
• 2. CD4+ Th1 cells
• Provide cytokine-dependent (mostly IFN-γ-dependent) help to
macrophages for intracellular killing of various microorganisms
• 3. CD4+ Th2 cells
• Produce IL-4, IL-5 and IL-13
• Recruit and activate eosinophils and other cell required to fight helminth
infections
• 4. CD4+ Th17 cells
• Produce IL-17 and IL-22 cytokines that recruit neutrophils to the skin and
lungs to fight bacterial and fungal infections
• 5. CYTOTOXIC CD8+ T cells- kill infected cells
• 6. REGULATORY T cells (Treg)
• Essential for controlling inflammation (notably reactivity to commensal
bacteria in the gut) and autoimmunity
A. SEVERE COMBINED
IMMUNODEFICIENCIES (SCIDs)
• Characterized by a gross functional impairment of both humoral and
cell-mediated immunity
• Incidence: 1 in 50,000 live births

• MANIFESTATIONS:
• Clinical consequences of the T cell deficiency usually occur within 3-6 months
of birth
• Susceptibility to devastating bacterial, fungal and viral infections frequently
manifesting as:
• Recurrent oral candidiasis
• Failure to thrive
• Protracted diarrhea
• Acute interstitial pneumonitis caused by Pneumocystis jiroveci
• Complications related to infections caused by live vaccines (notably bacille
Calmette-Guerin or BCG) that may lead not only to local and regional
infection but also to disseminated infection manifested by fever,
splenomegaly and skin and lytic bone lesions
• Scaly skin eruptions
A. SEVERE COMBINED
IMMUNODEFICIENCIES (SCIDs)
• DIAGNOSIS:
• Suspected based on a patient’s clinical history and possibly a
family history of deaths in very young children (suggestive of an
X-linked or recessive inheritance)

• Lymphocytopenia (90%)

• Absence of a thymic shadow on a CXR

• An accurate diagnosis relies on precise determination of the

number of circulating T, B and NK lymphocytes and their subsets
CAUSATIVE MECHANISMS for the
SCIDs:
A. SEVERE COMBINED
IMMUNODEFICIENCIES (SCIDs)
• 5 CAUSATIVE MECHANISMS for SCID:

• 1) CYTOKINE-SIGNALING DEFICIENCY (40-50%)

• Characterized by the absence of both T and NK cells

• 2) PURINE METABOLISM DEFICIENCY (10-20%)

• Deficiency in ADENOSINE DEAMINASE (ADA), an enzyme of purine
metabolism that deaminates adenosine (ado) and deoxyadenosine
(dAdo)
• An ADA deficiency results in the accumulation of ado and dAdo
metabolites that induce premature cell death of lymphocyte progenitors
and results in the absence of B and NK lymphocytes as well as T cells
• MANIFESTATIONS:
• Bone dysplasia with abnormal costochondral junctions and metaphyses
• PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY
• Cause severe and selective deficiency of T lymphocyte function
• Result in intracellular accumulation of deoxyguanosine triphosphate that trigger
apoptosis of immature T and B lineage cells
• Manifest as severe neurologic impairment
A. SEVERE COMBINED
IMMUNODEFICIENCIES (SCIDs)
• 3) DEFECTIVE REARRANGEMENTS of T and B CELL RECEPTORS
(20-30%)
• Autosomal recessive inheritance
• Result from mutations in genes encoding proteins that mediate the
recombination of V(D)J gene elements in T and B cell antigen
receptor genes (required for the generation of diversity in antigen
recognition)
• The main deficiencies involve RAG-1, RAG-2, DNA-dependent protein
kinase and Artemis

• 4) DEFECTIVE (PRE-) T CELL RECEPTOR SIGNALING in the

THYMUS
• Include deficiencies in CD3 subunits associated with the (pre-) TCR
(i.e., CD3δ, ε and ζ) and CD45.
A. SEVERE COMBINED
IMMUNODEFICIENCIES (SCIDs)
• 5) RETICULAR DYSGENESIS
• An extremely rare form of SCID that is due to a deficiency in
ADENYLATE KINASE 2 and results in T and NK deficiencies
• MANIFESTATIONS:
• Severe neutropenia
• Sensorineural deafness

• TREATMENT:
• Aggressive anti-infective therapies
• Immunoglobulin replacement
• Parenteral nutrition support
• HSCT
• Gene therapy
B. THYMIC DEFECTS
• 1. DiGEORGE SYNDROME:
• Results from maldevelopment of thymic epithelial elements derived from the 3rd
and 4th pharyngeal pouches
• Gene defect: hemizygous deletion in the long arm of chromosome 22
• MANIFESTATIONS:
• Congenital cardiac defects involving the great vessels
• Hypocalcemic tetany due to failure of parathyroid development
• Facial abnormalities: abnormal ears, shortened philtrum, micrognathia, hypertelorism

• 2. CHARGE SYNDROME:
• Coloboma of the eye, Heart anomaly, Choanal Atresia, Retardation and Ear
anomalies)

• 3. NUDE SYNDROME:
• Caused by mutations of the whn (whinged-helix-nude) gene that result in
impairment of hair follicle and epithelial thymic development
• MANIFESTATIONS:
• Congenital baldness
• Nail dystrophy
• Severe T cell immunodeficiency
C. OMENN SYNDROME
• A consequence of hypomorphic mutations in T cells

• MANIFESTATIONS:
• Early-onset erythrodermia
• Alopecia
• Hepatosplenomegaly
• Failure to thrive
• Lymphocytosis, eosinophilia, low B cell counts, low T cell TCR heterogeneity
• Impaired homeostasis of differentiating T cells causes the immune system-
associated disease

• TREATMENT:
• Anti-infective therapy
• Nutritional support
• Immunosuppression
• HSCT
D. FUNCTIONAL T CELL
DEFECTS
• Autosomal dominant mode of inheritance
• Characterized by partially preserved T cell differentiation but defective
activation resulting in abnormal effector function

• MANIFESTATIONS:
• Susceptibility to viral and opportunistic infections
• Chronic diarrhea
• Failure to thrive

• DIAGNOSIS:
• Phenotyping
• Functional assays

• EXAMPLES:
• 1. Zeta-associated Protein 70 (ZAP70) Deficiency
• 2. Calcium signaling defects
• 3. Human Leukocyte Antigen (HLA) Class II Deficiency
• 4. HLA Class I Deficiency
1. ZETA-Associated PROTEIN
70 (ZAP70) DEFICIENCY
• ZAP70 TYROSINE KINASE:
• A pivotal component in the TCR/CD3 signal transduction cascade

• Mutations in both alleles of the ZAP70 gene results in:

• a selective deficiency or almost complete absence of CD8 T cells
• dysfunction of CD4 T cells despite normal numbers

• MANIFESTATIONS:
• Recurrent opportunistic infections that begin within the first year
of life
2. CALCIUM SIGNALING
DEFECTS
• Caused by a mutation in the calcium channel gene (ORAI-) or
its activator (STIM-1)

• Defective antigen receptor-mediated Ca2+ influx result in a

profound defect in in vitro T and B cell activation

• MANIFESTATIONS:
• Functional T cell defects
• Autoimmune manifestations (blood cytopenias)
• Non-progressive muscle disease
3. HLA CLASS II DEFICIENCY:
• Hallmark of a group of 4 recessive genetic defects:
• RFX5
• RFXAP
• RFXANK
• CIITA

• Defective expression of HLA Class II molecules result in:

• low but variable CD4+ T cell counts
• defective antigen-specific T and B cell responses

• MANIFESTATIONS:
• Susceptibility to herpesvirus, adenovirus and enterovirus infections
• Chronic gut/liver Cryptosporidium infections
4. HLA CLASS I DEFICIENCY
• Defective expression of molecules involved in antigen
presentation by HLA Class I molecules:
• TAP-1
• TAP-2
• Tapasin

• Results in:
• Reduced CD8+ T cell counts
• Loss of HLA Class I antigen expression

• MANIFESTATIONS:
• Chronic obstructive pulmonary disease
• Severe vasculitis
E. T CELL PIDs with DNA
REPAIR DEFECTS
• 1. ATAXIA-TELANGIECTASIA (AT):
• Incidence: 1:40,000 live births
• Causes the following B cell defects:
• Low IgA
• IgG2 deficiency
• Low antibody production
• Associated with a progressive T cell immunodeficiency

• DEFECT:
• Caused by a mutation in the gene encoding the ATM protein- a
kinase that plays an important role in the detection and repair of
DNA lesions
• The defect in DNA repair mechanisms renders patients highly
susceptible to radiation-induced chromosomal damage and
resultant tumor development (lymphoma, leukemia, carcinomas)
E. T CELL PIDs with DNA
REPAIR DEFECTS
• 1. ATAXIA-TELANGIECTASIA (AT):
• MANIFESTATIONS:
• Truncal ataxia becomes evident when walking begins and is
progressive
• Oculocutaneous telangiectasia- dilated blood vessels in the ocular
sclera, and in a butterfly area on the face and of the ears
• Recurrent and chronic sinopulmonary infections leading to
bronchiectasis
• Other features: ovarian agenesis, high serum levels of oncofetal
proteins ( AFP, CEA)

• DIAGNOSIS:
• Cytogenetic analysis showing excessive chromsomal rearrangements
(mostly affecting chromosome 7 and 14) in lymphocytes
E. T CELL PIDs with DNA
REPAIR DEFECTS
• 2. NIJMEGEN BREAKAGE SYNDOME (NBS):
• Same cytogenetic abnormalities as AT
• Results from a deficiency in NIBRIN, a protein involved in DNA
lesions, caused by hypomorphic mutations
• Characterized by a severe T and B cell combined immune deficiency
with autosomal recessive inheritance
• MANIFESTATIONS:
• Microcephaly and a bird-like face
• High risk of malignancies

• 3. DYSKERATOSIS CONGENITA:
• Also known as Hoyeraal-Hreidarsson syndrome
• X-linked or autosomal recessive
• Caused by the mutation of genes encoding telomere maintenace
proteins, including DYSKERIN (DKC1)
E. T CELL PIDs with DNA
REPAIR DEFECTS
• MANIFESTATIONS:
• Characterized by a progressive immunodeficiency with:
• an absence of B and NK lymphocytes
• progressive bone marrow failure
• microcephaly
• in utero growth retardation
• gastrointestinal disease

• 3. IMMUNODEFICIENCY with CENTROMERIC and FACIAL ANOMALIES

(ICF):
• A complex syndrome of autosomal recessive inheritance characterized by a
mild T cell immune deficiency and a more severe B cell immune deficiency
• A consequence of a deficiency in the DNA METHYLTRANSFERASE resulting in
defective DNA methylation
• MANIFESTATIONS:
• Coarse face
• Digestive disease
• Mild mental retardation
F. T CELL PIDs with HYPER-
IgE
• 1. AUTOSOMAL RECESSIVE HYPER-IgE SYNDROME:
• Result from mutations in the DOCK8 gene
• MANIFESTATIONS:
• Recurrent bacterial infections in the skin and respiratory tract
• Severe skin and mucosal infections by pox viruses and HPV
• Severe allergy
• Low T and B lymphocytes
• TREATMENT: HSCT

• 2. Tyk-2 DEFICIENCY:
• Tyk 2 -a JAK family kinase involved in cytokine receptor signaling
• A rare condition with autosomal recessive inheritance
• Manifests with susceptibility to infection with various microbes
G. AUTOSOMAL DOMINANT
HYPER-IgE SYNDROME
• Characterized by elevated serum IgE levels

• DEFECTS:
• Defective TH17 effector responses
• Heterozygous (dominant) mutation in the gene encoding the transcription factor
STAT3 required in the signaling pathways following binding of cytokine to cytokine
receptors
• Partially defective antibody production because of defective IL-21R signaling

• MANIFESTATIONS:
• Recurrent skin and lung infections caused by pyogenic bacteria and fungi
complicated by pneumatoceles
• Facial dysmorphy
• Defective loss of primary teeth
• Hyperextensibility
• Scoliosis
• Osteoporosis

• TREATMENT: Immunoglobulin
H. CARTILAGE HAIR
HYPOPLASIA (CHH)
• Autosomal recessive

• DEFECT:
• Caused by mutations in the RMRP gene for a noncoding
ribosome-associated RNA

• MANIFESTATIONS:
• Characterized by a combined T and B cell PID with:
• Short-limb dwarfism
• Metaphyseal dysostosis
• Sparse hair
• Predisposition to erythroblastopenia, autoimmunity and tumors
I. CD40 LIGAND and CD40
DEFICIENCIES:
• HYPER-IgM SYNDROME (HIGM):
• An X-linked inheritance caused by a deficiency in CD40 ligand (L) or
rarely, a deficiency in CD40 itself
• CD40L: induces signaling events in B cells that are necessary for both
class switch recombination (CSR) and adequate activation of other CD40-
expressing cells involved in innate immune responses
• Results from defective immunoglobulin CSR in germinal centers and
leads to profound deficiency in production of IgG, IgA and IgE

• MANIFESTATIONS:
• Susceptibility to opportunistic infections
• Interstitial pneumonitis caused by Pneumocyctis jirovecii
• Protracted diarrhea and cholangitis caused by Cryptosporidium
• Brain infection by Toxoplasma gondii

• TREATMENT: HSCT
J. WISKOTT-ALDRICH
SYNDROME (WAS)
• A complex, recessive, X-linked disease
• Incidence: 1 in 200,000 live births
• DEFECT:
• Caused by a mutation in the WASP gene that affect not only T lymphocytes but
also other lymphocyte subsets, dendritic cells and platelets

• MANIFESTATIONS:
• Null mutation
• Invasive and bronchopulmonary infections
• Severe eczema
• Autoimmune disorders- due to defective regulatory T cells
• Antibody-mediated blood cytopenia
• Glomerulonephritis
• Skin and visceral vasculitis
• Erythema nodosum
• Arthritis
• Hypomorphic mutations: thrombocytopenia
• Lymphoma- virally induced (EBV or Kaposi’s sarcoma-associated herpesvirus)
• Thrombocytopenia may be compounded by the peripheral destruction of platelets
associated with autoimmune disorders
J. WISKOTT-ALDRICH
SYNDROME (WAS)
• DIAGNOSIS:
• Based on intracellular immunofluorescence analysis of WAS protein (WASp)
expression in blood cells
• WASp: regulates the actin cytoskeleton and thus plays an important role in the
following lymphocyte functions:
• Cell adhesion and migration
• Formation of synapses between antigen-presenting and target cells
• Relative CD8+ T cell deficiency
• Low serum IgM
• Decreased antigen-specific antibody responses
• Reduced sized platelets on blood smear

• TREATMENT:
• Prophylactic antibiotics
• IgG supplementation
• Topical treatment of eczema
• Splenectomy
• HSCT
TREATMENT of PRIMARY T
CELL IMMUNODEFICIENCY
• Symptomatic

• Thymic transplant to repair T cell deficiency- Nude, DiGeorge

syndrome

• Bone marrow transplantation after myeloablative

conditioning- PNP, MHC Class II deficiency

• Immunoglobulin infusions- for T cell-deficient individuals with

severe antibody deficiency reflected by low serum IgG levels

• Prophylactic therapy for opportunistic infections- TMP-SMX

for P. carinii infection
B CELL DIFFERENTIATION
and Related PIDs
II. B LYMPHOCYTE
DEFICIENCIES
• Ig ISOTYPES:
• IgM- found in the vascular compartment and are also secreted at mucosal surfaces
• IgG- diffuse freely into extravascular spaces
• IgA- produced and secreted predominantly from mucosa-associated lymphoid
tissues

• Effector functions include Fc receptor-mediated and C3 receptor-dependent

phagocytosis of microorganisms and the ability to recognize and neutralize a
given pathogen

• DEFECTIVE or DEFICIENT ANTIBODY PRODUCTION:

• Rarely occur before the age of 6 months due to the transient protection provided
by the transplacental passage of immunoglobulins during the last trimester of
pregnancy
• Susceptibility to invasive, pyogenic bacterial infections
• Recurrent sinus and pulmonary infections by Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis and Grgam-negative bacteria (less
common) which when left untreated lead to bronchiectasis and ultimately, coe
pulmonale and death
• Parasitic infections
A. AGAMMAGLOBULINEMIA
• 1. X-LINKED AGAMMAGLOBULINEMIA (85%):
• DEFECT:
• Caused by a mutation in the Bruton’s tyrosine kinase (BTK) gene located in the X
chromosome
• BTK GENE:
• a kinase that participates in (pre) B cell receptor signaling
• when defective, there is a block at the pre-B to B cell stage

• MANIFESTATIONS:
• Affected males begin to have recurrent sinopulmonary bacterial infections in the
first year of life when maternally derived IgG have disappeared
• Mycoplasma infections
• Encephalitis of viral etiology associated with dermatomyositis

• DIAGNOSIS: lack of BTK through detection by intracellular

immunofluorescence of monocytes

• TREATMENT: IV immunoglobulin
A. AGAMMAGLOBULINEMIA
• 2. AUTOSOMAL RECESSIVE AGAMMAGLOBULINEMIA (10%):
• DEFECTS:
• Mutations of the genes coding pre-B cell receptor components
blocking B lineage differentiation
• Mutations of genes coding transcription factors for pre-B receptor
genes or for key elements in the pre-B cell receptor signaling
pathway

• MANIFESTATIONS:
• Congenital absence of B cells
• Agammaglobulinemia
• Recurrent bacterial infections

• TREATMENT: Immunoglobulin replacement

B. HYPER-IgM (HIGM)
SYNDROME
• A rare B cell PID

• DEFECT:
• Defective Ig class switch recombination (CSR)
• Results in:
• Low serum levels of IgG and IgA
• Elevated or normal serum IgM levels

• MANIFESTATIONS:
• Chronic bacterial infections
• Pneumonia caused by unusual organisms (P. carinii, CMV, Aspergillus,
Cryptosporidium)
• Enteritis due to cryptosporidial infection extending into the biliary tract
resulting in sclerosing cholangitis and hepatic cirrhosis
• IgM-mediated autoimmunity
• Enlarged lymphoid organs and lymphomas- result from mutations in the gene
encoding activation-induced DEAMINASE, the protein that induces CSR in B
cell germinal centers
C. COMMON VARIABLE
IMMUNODEFICIENCY (CVID)
• An ill-defined and heterogenous group, mostly adults, who have in common the
clinical manifestations of all the different classes of Ig isotypes

• DEFECT:
• B lymphocytes are able to recognize antigen and can proliferate in response, but
they fail to become memory B cells and mature plasma cells
• The abortive differentiation pattern leads to the occurrence of nodular B
lymphocyte hyperplasia and lymphoproliferation, resulting in:
• spenomegaly
• intestinal lymphoid hyperplasia

• MANIFESTATIONS:
• Chronic pulmonary infections and bronchiectasis
• Intestinal diseases- chronic giardiasis, intestinal malabsorption, atrophic gastritis
with pernicious anemia, colitis
• Granulomatous lesions
• Antibody-mediated autoimmune disease
• Lymphoid malignancies

• TREATMENT: IV Ig
D. SELECTIVE Ig ISOTYPE
DEFICIENCIES
• 1. IgA DEFICIENCY:
• An inability to produce antibodies of the IgA1 and IgA2 subclasses
• Incidence: 1:600 individuals of European origin

• DEFECT: block in B cell differentiation that may reflect defective

interaction between T and B cells

• MANIFESTATIONS:
• Asymptomatic in most cases
• Recurrent respiratory infections leading to progressive pulmonary
disease and bronchiectasis
• Chronic diarrheal diseases
• Increased susceptibility to drug allergies, atopic disorders and
autoimmune diseases (arthritis, SLE)

• TREATMENT: symptomatic, immunoglobulin replacement

D. SELECTIVE Ig ISOTYPE
DEFICIENCIES
• 2. IgG DEFICIENCY:
• Selective deficiencies in 1 or more of the 4 IgG subclasses

• DEFECT:
• Homozygous deletions of genes encoding the constant region of the
different γ chains

• MANIFESTATION:
• Recurrent sinopulmonary infections
• IgA deficiency may accompany IgG2 and IgG4 subclass deficiencies

• TREATMENT: Immunoglobulin replacement

E. TRANSIENT
HYPOGAMMAGLOBULINEMIA of
INFANCY
• Refer to those rare instances in which the normal physiologic
hypogammaglobulinemia of infancy is unusually prolonged
and severe

• IgG levels normally drop to 3.0 to 4.0 g/L between 3 and 6

months of age as maternally derived IgG is catabolized which
then subsequently rise, reflecting the infant’s increased
synthetic capacity

• TREATMENT:
• Antibody replacement therapy only in the face of severe or
recurrent infection
TREATMENT of Ig
DEFICIENCY SYNDROMES:
• 1. IMMUNOGLOBULIN REPLACEMENT:
• Therapeutic cornerstone for antibody-deficient patients who have recurrent
infections and deficient in IgG
• Target serum IgG levels: > 5.0g/L
• ROUTES of ADMINISTRATION:
• 1. INTRAVENOUS
• 400-500mg/kg repeated every 3-4 weeks
• Residual target of 800mg/mL
• 2. SUBCUTANEOUS
• Performed once a week then adjusted on a case-to-case basis
• A trough level of 800mg/mL is a desirable target

• 2. SYMPTOMATIC:
• Anti-infective therapy to target recurrent or devastating bacterial, fungal or
parasitic infections
• Antibiotic treatment for recurrent sinopulmonary H. influenzae infections
• G. lamblia- Metronidazole
• Cryptosporidial infections- Amphotericin B or Flucytosine

• 3. BONE MARROW TRANSPLANTATION (BMT) or HEMATOPOIETIC STEM CELL

TRANSPLANTATION (HSCT)
 PRIMARY
IMMUNODEFICIENCIES
AFFECTING
REGULATORY PATHWAYS
I. HEMAPHAGOCYTIC
LYMPHOHISTIOCYTOSIS (HLH)
• Characterized by an unremitting activation of CD8+ T lymphocytes and
macrophages that leads to organ damage to the liver, bone marrow and
the central nervous system (CNS)
• DEFECT: Impaired T and NK lymphocyte cytotoxicity

• MANIFESTATIONS:
• Often induced by a viral infection- EBV is the most frequent trigger
• Onset may start during the first year of life or even at birth
• Characteristic symptoms:
• Fever
• Hepatosplenomegaly
• Edema
• Neurologic diseases
• Blood cytopenia
• Increased liver enzymes
• Hypofibrinogenemia
• High triglyceride levels
• Elevated markers of T cell activation
• Hemaphagocytic features in the bone marrow or CSF
I. HEMAPHAGOCYTIC
LYMPHOHISTIOCYTOSIS (HLH)
• Classified into 3 subsets:
• 1) FAMILIAL HLH- autosomal recessive inheritance
• A) perforin deficiency (30%)
• B) Munc13-4 deficiency (30%)
• C) syntaxin 11 deficiency (10%)
• D) Munc18-2 deficiency (20%)
• E) others (10%)
• 2) HLH with partial albinism
• A) Chediak-Higashi syndrome
• B) Griscelli syndrome
• C) Hermansky Pudlak syndrome type II
• 3) X-linked proliferative (XLP) syndrome
• Occurs following EBV infection
• Manifested as:
• Low 2B4-mediated NK cell cytotoxicity
• Impaired differentiation of NKT cells
• Defective antigen-induced T cell death
• Defective T helper activity for B cells
• TREATMENT:
• Immunosuppression- etoposide, anti-T cell antibodies
• HSCT
II. AUTOIMMUNE
LYMPHOPROLIFERATIVE SYNDROME
(ALPS)
• DEFECT:
• Heterozygous mutation in the gene encoding Fas characterized by
dominant inheritance and variable penetrance
• Fas-mediated apoptosis of lymphocytes, which accumulate and
mediate autoimmunity

• MANIFESTATIONS:
• Nonmalignant T and B lymphoproliferation causing splenomegaly
and enlarged lymph nodes
• Autoimmune manifestations
• Autoimmune cytopenias
• Guillain-Barre syndrome
• Uveitis
• Hepatitis

• TREATMENT: Proapoptotic drugs

III. IMMUNODYSREGULATION
POLYENDOCRINOPATHY ENTEROPATHY
X-LINKED SYNDROME (IPEX)
• DEFECT:
• Loss-of-function mutations in the gene encoding the transcription
factor FOXP3, which is required for the acquisition of effector
function by regulatory T cells

• MANIFESTATIONS:
• widespread inflammatory enteropathy and food intolerance
• skin rashes
• autoimmune cytopenias
• diabetes

• TREATMENT:
• Immunosuppression
• HSCT
IV. AUTOIMMUNE
POLYENDOCRINOPATHY CANDIDIASIS
ECTODERMAL DYSPLASIA (APECED)
• DEFECT:
• Mutations in the autoimmune regulator (AIRE) gene and results
in autoimmune manifestations due to:
• impaired thymic expression of self-antigens by medullary epithelial
cells
• impaired negative selection of self-reactive T cells

• MANIFESTATIONS:
• Multiple autoimmune manifestations that affect solid organs in
general and endocrine glands in particular
• Mild, chronic Candida infection
• Ectodermal dysplasia
 AUTOIMMUNITY
and
AUTOIMMUNE DISEASES
AUTOIMMUNITY vs.
AUTOIMMUNE DISEASE
• AUTOIMMUNITY:
• Refers merely to the presence of antibodies or T lymphocytes
that react with self-antigens and does not necessarily imply that
the self-reactivity has pathogenic consequences

• AUTOIMMUNE DISEASE:
• Tissue injury is caused by the immunologic reaction of the
organism against its own tissues

• Autoimmunity is present in all individuals ; however,

autoimmune disease occurs in those individuals in whom the
breakdown in one or more of the basic mechanisms regulating
immune tolerance results in self-reactivity and cause tissue
damage
MECHANISMS PREVENTING
AUTOIMMUNITY
• 1. Sequestration of self-antigens, rendering them inaccessible to the
immune system

• 2. Specific unresponsiveness (tolerance or anergy) of relevant T and

B cells and maintenance of tolerance
• a. central deletion of autoreactive lymphocytes
• b. peripheral anergy of autoreactive lymphocytes
• c. receptor replacement in autoreactive lymphocytes

• 3. Limitation of potential reactivity by regulatory mechanisms

• a. regulatory T cells
• b. regulatory B cells
• c. regulatory mesenchymal cells
• d. regulatory cytokines
• e. idiotype network
MECHANISMS of
AUTOIMMUNITY
• I. EXOGENOUS (bacterial or viral)
• A. Molecular mimicry (cross-reactivity)- RF, T1DM, RA, MS
• B. Superantigenic stimulation- Staphylococcal protein A and enterotoxins
• C. Microbial and tissue damage-associated adjuvanticity
• II. ENDOGENOUS
• A. Altered antigen presentation
• 1. loss of immunologic privilege
• 2. presentation of novel or cryptic epitopes (epitope spreading)
• 3. alteration of self-antigen
• 4. enhanced function of antigen-presenting cells
• a. costimulatory molecule expression
• b. cytokine production
• B. Increased T cell help
• 1. cytokine production
• 2. costimulatory molecules
• C. Increased B cell function
• 1. B cell activating factor
• 2. costimulatory molecules
• D. Apoptotic defects or defects in clearance of apoptotic material
• E. Cytokine imbalance
• F. Altered immunoregulation
• G. Endocrine abnormalities
MECHANISMS of
AUTOIMMUNITY
• No single mechanism can explain all the varied manifestations
of autoimmunity

• A number of abnormalities need to converge to induce an

autoimmune disease

• Additional factors that appear to be important determinants

in the induction of autoimmunity:
• Age
• Sex (women>men)
• Genetic background
• Exposure to infectious agents
• Environmental contacts
IMMUNOPATHOGENIC
MECHANISMS in AUTOIMMUNE
DISEASE
• The mechanisms of tissue injury in autoimmune diseases can be
divided into antibody-mediated and cell-mediated processes

• A. the pathogenicity of autoantibodies can be mediated through the

following mechanisms:
• 1. opsonization of soluble factors or cells
• 2. activation of the inflammatory cascade via the complement system
• 3. interference with the physiologic function of soluble molecules or
cells

• B. mechanisms of cell-mediated immunity:

• 1. cytokine production
• 2. cellular cytotoxicity
MECHANISMS of TISSUE DAMAGE
in AUTOIMMUNE DISEASE
HUMAN AUTOIMMUNE DISEASE:
PRESUMPTIVE EVIDENCE for
IMMUNOLOGIC PATHOGENESIS
DISEASES on the
AUTOIMMUNE SPECTRUM
ORGAN-SPECIFIC
AUTOIMMUNE DISEASE:
• One important feature is the tendency for overlap, such that
an individual with one specific syndrome is more likely to
develop a second syndrome

• More striking is the tendency for individuals with an organ-

specific autoimmune disease to develop multiple other
manifestations of autoimmunity without the development of
associated organ pathology
• High incidence of pernicious anemia in individuals with
autoimmune thyroiditis

• Part of the explanation for this may relate to the genetic

elements shared by individuals with these different diseases
SYSTEMIC AUTOIMMUNE
DISEASES
• Systemic autoimmune diseases differ from organ-specific
diseases in that pathologic lesions are found in multiple,
diverse organs and tissues

• The hallmark of systemic autoimmune diseases is the

demonstration of associated relevant autoimmune
manifestations that are likely to be etiologic in the organ
pathology
TREATMENT
• GOALS:
• 1) suppression of the induction of autoimmunity
• 2) restoration of normal regulatory mechanisms
• 3) inhibition of the effector mechanisms

• IMMUNOSUPPRESSIVE or ABLATIVE THERAPIES- eliminate autoreactive

cells

• CYTOKINE BLOCKADE- prevent immune activation, targeting TNF or IL-1

• Therapies that target lymphoid cells:

• Blockage of costimulatory signals neded for T or B cell activation
• Elimination of effector T or B cells
• Use of autoantigen to induce tolerance

• Therapies that prevent target organ damage or support target organ

function