Inmunodeficiencia

ObjectivesDefinitionPrimary Immunodeficiencies

CharacteristicsTypes of primary immunodeficiency disordersMode of inheritanceDiagnosis and Treatment

ImmunodeficiencyDefect in 1 or more components of immune system

Types:Primary or Congenital:

Born with the immunodeficiency Inherited (Mutation in gene controlling immune cells)Susceptible to recurrent, severe infection; starting in

childrenCannot recover without treatment>150 immunodeficiency disorders

Hematopoiesis

Progenitor

Progenitor

Hematopoietic Stem Cell (HSC) deficiencyHSC are multipotent (differentiate into all blood cell types)Self renewing cellsLineage negative (mature B/T cell, granulocyte, Mφ markers

absent)CD34+, c-Kit+, Stem cell Ag (Sca-1+) on cell surfaceDefect in HSC results in Reticular DysgenesisAffects development of all leukocytesPatients are susceptible to all infections (bacterial, viral,

parasitic and fungal)Fatal without treatmentTreated with bone marrow or HSC transplantation

TCR

Allogeneic BM/HSC Transplantation

HSC

Thymus

Thymic Stromal Cells

MHC

T cell

MHC

T cell

MHC-matched for atleast1-2 allelesT cell depleted

TCR

T cells

Hematopoiesis

Progenitor

Progenitor

Myeloid Progenitor Cell Differentiation DefectMyeloid Progenitor Cells develop into neutrophils and

monocytesDefect in differentiation from myeloid progenitor cells

into neutrophils results in

Congenital AgranulocytosisRecurrent bacterial infections seen in patientsTreated with granulocyte-macrophage colony

stimulating factor (GM-CSF) or G-CSF

Defective NeutrophilsPatients have neutrophils that are defective in

production of reactive oxygen species that is responsible for killing of phagocytosed microrganisms.

Nitroblue tetrazolium test: reduction by superoxide (-ve)

This results in accumulation of granulocytes, Mφ and T cells forming granulomas. These patients suffer from

Chronic Granulomatous Disease.Have recurrent bacterial infectionsCommensals become pathogenicX-linked or autosomal recessiveTreated with IFN-γ against infections

Inheritance22 pairs of autosomes and 1 pair of sex chromosomes (X and Y)Autosomal recessive (most AA normal; Aa carrier; aa affected)Autosomal dominant (Aa affected; aa is normal)X-linked (XX carrier daughter; XY affected son)

Carrier x CarrierMother Father Aa Aa

Normal x Affected Mother Fatheraa Aa

Carrier x NormalMother FatherXx XY

Autosomal Recessive Autosomal Dominant X-linked

Leukocyte Adhesion deficiency

Adhesion molecule (e.g.CD18) may be lacking on T cells and monocytes.

Autosomal recessiveResults in defective extravasationRecurrent infectionsImpaired wound healingTreated with BM (depleted of T cells and

HLA matched) transplantation

or with gene therapy

Hematopoiesis

Progenitor

Progenitor

Defect in Lymphoid ProgenitorResults in Severe Combined Immunodeficiency (SCID)Lack T, B and/or NK cellsThymus does not developMyeloid and erythroid cells are normal.Generally lethalSusceptible to bacterial, viral and fungal infections.In infants, passively transferred maternal Abs are present.Live attenuated vaccines (e.g. Sabin polio) can cause disease.

Types of SCIDRAG-1/2 (Recombinase activating gene) deficiency: Required for

TCR and Ig gene rearrangement

IL-2R gene defect

Adenosine deaminase (ADA) deficiency

Adenosine Inosine Uric acid

T, B and NK cell deficiency due to toxicity of accumulated metabolites

First successful gene therapy done in patient

T cells/NK

cells

IL-2 receptor

IL-2

TCRT

cells

B cells

Ig

ADA

DiGeorge syndrome

Precursor T cell differentiation defectAthymic - DiGeorge SyndromeLack of T helper (Th) cells , Cytotoxic T cells (CTL) and T

regulatory (Treg) cellsB cells are present but T-dependent B cell responses are

defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart diseaseTreated with thymic transplant Autosomal dominant trait

Nude Athymic mouse

nu/nu gene (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts

Hyper IgM Syndrome

Absence of Igs and B cellsArrest at Pre-B cell stage (H-chain rearranged not L chain)

Deficiency in IgG, IgA and IgEIncreased IgM in serumB cells express IgD and IgM on membraneX-linkedRecurrent infections

e.g. IgA deficiency Due to defect in isotype switchingRecurrent respiratory, gastrointestinal and/or

genitourinary infection

Selective Ig class deficiency

X-linked Agammaglobulinemia (x-LA)

Pre B cells

Mature B cells

x-LA

Proliferation

DifferentiationIsotype switchingCVD

IgA def.

Plasma cells

IgM

Common Variable ImmunodeficiencyB cells are normalDefect in maturation to plasma cells Decreased IgM, IgG and IgA or only IgG and IgASusceptible to bacterial (e.g. pneumococci) infectionsLow Ab titers against DPT or MMR VaccinesUsually not detected in children because of

maternal AbsAlso called Late-onset hypogammaglobulinemia,

Adult-onset agammaglobulinemia or Acquired

agammaglobulinemiaIg replacement therapy and antibiotics

Pre B cells

Mature B cells

x-LA

Proliferation

DifferentiationIsotype switchingCVD

IgA def.

Plasma cells

IgM

Other ImmunodeficienciesBare lymphocyte syndrome:

Lack MHC class II on B cells, macrophages and dendritic cells

Complement Deficiency

x-linkedaγglobulinemiaxLA DiGeorge

Syndrome d

Common Variable Hypoγglobulinemia / x-linked hyperIgM syndrome/Selective Ig deficiency

Primary ImmunodeficienciesStem Cell

Myeloid Progenitor

Lymphoid Progenitor

Neutrophil Monocyte Pre-B Pre-T

Mature B

PlasmaCell Memory B

Thymus

Reticular Dysgenesis

Severe combined ImmunodeficiencySCID

Congenital Agranulocytosis

Chronic GranulomatousDisease (x or r)

Bare Lymphocyte Syndrome

Mature T

Adaptive Immunity DeficiencyT cell deficiency

Susceptible to intracellular bacterial infection

e.g. Salmonella typhi, Mycobacteria Susceptible to viral, parasitic and fungal infection

B cell deficiencySusceptible to extracellular bacterial infection e.g.

Staphylococcal infection