Defects in Adaptive Immunity

Slide 1 · Defects in Adaptive Immunity

Primary immunodeficiencies of lymphocyte maturation, activation and immune regulation

T-cell arm

Cell-mediated immunity

B-cell arm

Antibody production

Regulatory arm

Tolerance and balance

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish defects of lymphocyte development from defects of immune activation and regulation.

Explain genotype-to-phenotype links in the major adaptive immunodeficiencies.

Predict infection patterns and lymphoid morphology from the affected immune compartment.

Compare key disorders using immune-cell populations and immunoglobulin profiles.

Slide 3 · Adaptive immunity requires three linked processes

Development

Generate competent mature T and B lymphocytes

Activation

Recognize antigen and transmit functional signals

Effector output

Produce antibodies, cellular immunity and memory

The defect may arise at any step; Immune regulation overlays the process

Slide 4 · T-cell and B-cell defects are not independent

T-cell dysfunction

Loss of cell-mediated microbial control

Reduced helper signals to B lymphocytes

Secondary impairment of antibody synthesis

B-cell dysfunction

Poor immunoglobulin production

Reduced antibody-mediated opsonization

T-cell-mediated responses can be preserved

Slide 5 · A molecular defect can produce a clinical immune phenotype

Genetic lesion

Receptor, kinase, enzyme or transcriptional regulator

Functional block

Deficient lymphocyte number or activity

Clinical result

Specific infection susceptibility and immune dysregulation

Slide 6 · Classify disorders by primary functional bottleneck

Bottleneck

Source examples

Combined lymphocyte dysfunction

SCID; MHC class II deficiency

B-cell maturation

X-linked agammaglobulinemia

Thymic / T-cell development

DiGeorge syndrome

Helper signals and Ig diversification

Hyper-IgM syndrome

Late antibody differentiation

CVID; selective IgA deficiency

Cytotoxic control / regulation

X-linked lymphoproliferative disease; PIRDs

Slide 7 · Microbial patterns reflect the defective immune task

Broad bacterial, fungal and viral vulnerability suggests a combined defect such as SCID.

Recurrent pyogenic respiratory infections point toward deficient antibody-mediated opsonization.

Severe EBV infection is particularly characteristic of X-linked lymphoproliferative disease.

Mucosal infections are a principal clue to deficient IgA-mediated defense.

Slide 8 · SCID is a shared phenotype, not one mutation

Severe combined immunodeficiency (SCID) comprises genetically distinct disorders.

Both humoral and cell-mediated responses are profoundly impaired.

A primary T-cell abnormality may also prevent effective B-cell antibody production.

Developmental failure occurs at different points in the lymphocyte lineage.

Slide 9 · SCID presents early with widespread infection susceptibility

Typical infant clues: Oral candidiasis, severe diaper dermatitis and failure to thrive.

Infections can involve Candida, Pneumocystis, cytomegalovirus, varicella and pyogenic bacteria.

Untreated disease is life-threatening in infancy; Hematopoietic stem-cell transplantation.

Slide 10 · Why severe T-cell loss also causes antibody failure

Defective T lineage

Few functional T helper cells

Missing B-cell help

Poor T-dependent activation of B cells

Combined phenotype

Impaired cellular immunity plus antibody synthesis

Slide 11 · Maternal T cells may cause neonatal GVHD in SCID

Maternal lymphocytes can cross the placenta and persist in an immunodeficient infant.

These transferred cells may attack host tissues and cause a morbilliform eruption.

The rash reflects graft-versus-host disease, not a competent protective infant T-cell response.

Slide 12 · X-linked SCID: Common γ-chain signaling failure

Common γ-chain defect

Shared signaling component of several cytokine receptors

IL-7 response impaired

Poor survival and expansion of developing T cells

T-cell deficiency

Severely reduced T cells; Ineffective humoral response

Slide 13 · The IL-15 pathway explains an NK-cell deficit

Common γ-chain defective

IL-15 receptor signaling cannot function normally

NK maturation impaired

Reduced development and proliferation of NK cells

Characteristic pattern

T cells low; NK cells often low; B cells may be present

Slide 14 · Lymphocyte number and function must be separated

X-linked SCID: Cell numbers

T cells markedly reduced

B cells can be normal in number

NK cells often deficient

X-linked SCID: Function

Cell-mediated immunity severely reduced

T-dependent antibody synthesis ineffective

Recurrent infections across pathogen classes

Slide 15 · ADA deficiency: Toxic metabolites impair lymphopoiesis

ADA deficiency

Purine metabolism is disrupted

Metabolite accumulation

Deoxyadenosine and deoxy-ATP build up

Lymphocyte toxicity

Rapidly dividing immature lymphocytes are injured

Slide 16 · ADA-SCID often depletes T cells more than B cells

The toxic metabolite model predicts marked injury to proliferating lymphoid precursors.

T-lineage lymphocytes may be reduced more severely than B-lineage cells.

The precise mechanistic contribution of accumulated metabolites is described as incompletely resolved.

Slide 17 · RAG defects block assembly of antigen receptors

RAG machinery defective

V(D)J recombination cannot proceed properly

No functional TCR / Ig genes

Developing lymphocytes fail their receptor checkpoint

T- and B-cell block

Both adaptive lymphocyte lineages are affected

Slide 18 · JAK3 mutation phenocopies common γ-chain failure

JAK3 defective

Intracellular cytokine receptor signaling impaired

γ-chain pathway lost

Same broad developmental signaling deficit

SCID phenotype

Major T-lineage developmental impairment

Slide 19 · Additional SCID lesions impair T-cell receptor signaling

Some disorders involve receptor chains, TCR-associated kinases or other signaling components.

Abnormal calcium entry can also prevent normal lymphocyte activation.

These mechanisms illustrate that profound immunodeficiency can arise after lymphocytes are initially generated.

Slide 20 · SCID histology reflects failed lymphocyte maturation

Thymus

Small organ with marked lymphocyte depletion

γ-chain disease may resemble fetal thymic epithelium

ADA deficiency may retain Hassall corpuscle remnants

Peripheral lymphoid tissue

Lymphoid organs are hypoplastic

Marked depletion of T-cell regions

Some forms also deplete B-cell compartments

Slide 21 · Cell loss predicts the anatomy of lymphoid depletion

Thymic T-cell failure

Few mature T lymphocytes available

Peripheral homing reduced

Lymph-node paracortex and splenic T zones depleted

Poor immune tissue growth

General lymphoid hypoplasia

Slide 22 · SCID: Four lesions, four mechanistic targets

Affected component

Primary mechanistic failure

Implication

Common γ-chain

Multiple cytokine receptor signals

T-cell development; often NK development

ADA

Purine metabolite clearance

Toxicity to developing lymphocytes

RAG proteins

Antigen receptor gene rearrangement

T and B receptor assembly

JAK3

Downstream cytokine-receptor signaling

γ-chain-like developmental phenotype

Slide 23 · Stem-cell transplantation addresses the developmental block

Hematopoietic stem-cell transplantation as the main SCID treatment.

Donor-derived progenitors can generate functional immune lineages.

The target is durable immune reconstitution, rather than treating each infection in isolation.

Slide 24 · Ex vivo gene correction: Conceptual treatment sequence

Collect HSCs

Obtain autologous hematopoietic stem cells

Introduce functional gene

Use a vector to supply the missing gene

Return corrected cells

Reinfuse cells to restore immune development

Slide 25 · Early SCID gene therapy exposed insertional oncogenesis

Early viral-vector treatment of X-linked SCID achieved immune reconstitution in some patients.

Integration near growth-control genes caused T-cell lymphoblastic leukemia in some early trials.

The development of vectors designed to reduce this risk.

These historical trial outcomes must not be treated as contemporary treatment-rate estimates.

Slide 26 · ADA-SCID has multiple source-described replacement strategies

Hematopoietic stem-cell transplantation replaces the affected lymphoid progenitors.

Enzyme administration is described as another approach.

Gene transfer into lymphoid precursors is also discussed.

Specific protocols and current indications are outside the supplied source excerpt.

Slide 27 · Clinical reasoning: A newborn with opportunistic infections

Illustrative vignette

An infant has persistent oral candidiasis, extensive diaper rash, failure to thrive and severe respiratory infection.

Which broad immune compartment is most likely defective?

Interpretation: A combined deficiency is more consistent with this spectrum than an isolated late-onset antibody defect.

Slide 28 · Normal B-cell development uses the pre-BCR checkpoint

Heavy chain formed

Ig heavy-chain rearrangement begins in pre-B cells

Pre-BCR signals

Surrogate light chain and heavy chain form a receptor

Light-chain rearrangement

Successful signaling supports further B-cell maturation

Slide 29 · BTK mutation arrests B-cell maturation

BTK signaling lost

Pre-BCR cannot transmit a normal signal

Maturation arrests

Progression from pre-B cell to mature B cell fails

Antibody absent

Few mature circulating B cells and plasma cells

Slide 30 · Why X-linked agammaglobulinemia appears after infancy

The disorder predominantly affects boys because the classic gene defect is X-linked.

Maternal immunoglobulins offer temporary passive protection.

Clinical infections commonly become apparent around 6 months as maternal antibodies wane.

Slide 31 · Encapsulated and pyogenic bacteria expose absent antibodies

Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus are textbook examples.

Recurrent otitis, sinusitis, bronchitis and pneumonia are common presentations.

Poor antibody opsonization weakens phagocytic clearance of these organisms.

Slide 32 · Enteroviruses are an important non-pyogenic exception

Antibodies also neutralize some viruses before systemic dissemination.

Echovirus, coxsackievirus and poliovirus vulnerability.

Enteroviruses can spread from the gastrointestinal tract to the nervous system.

Live poliovirus vaccination is specifically described as hazardous in this condition.

Slide 33 · Giardia reflects loss of mucosal antibody defense

Secreted IgA contributes to resistance against intestinal Giardia lamblia.

Antibody deficiency can permit persistent protozoal infection.

Preserved T-cell-mediated immunity still supports control of many fungal and intracellular infections.

Slide 34 · X-linked agammaglobulinemia: Tissue and blood

Circulating / marrow

Mature blood B cells absent or markedly low

All serum immunoglobulin classes reduced

Pre-B lineage cells remain in marrow

Lymphoid tissue

Germinal centers poorly developed

Plasma cells are absent or markedly depleted

T-cell responses remain functional

Slide 35 · Why germinal centers and plasma cells are missing

B-cell maturation fails

Few mature naive B lymphocytes available

Germinal-center input lost

Little antigen-driven follicular response

Plasma-cell output lost

Minimal immunoglobulin production

Slide 36 · Replacement immunoglobulin targets antibody function

Immunoglobulin replacement is described as treatment for X-linked agammaglobulinemia.

It compensates for deficient protective antibodies without correcting the BTK lesion.

The source reports substantially improved survival with prophylactic IVIG.

Slide 37 · Autoimmune disease can coexist with profound antibody loss

Arthritis and dermatomyositis are described despite severe hypogammaglobulinemia.

The source suggests dysregulated self-tolerance or infection-driven inflammation as possibilities.

The mechanism is not presented as definitively established.

Slide 38 · Distinguish X-linked SCID from agammaglobulinemia

Feature

X-linked SCID

X-linked agammaglobulinemia

Main lesion

Common γ-chain

BTK

T lymphocytes

Greatly reduced

Preserved

B lymphocytes

May be present; poorly functional

Mature B cells markedly reduced

Signature risk

Broad opportunistic infections

Recurrent pyogenic / enteroviral infections

Slide 39 · DiGeorge syndrome originates in embryologic development

Pharyngeal pouch anomaly

Abnormal third and fourth pouch derivatives

Thymic hypoplasia

Reduced organ for T-cell maturation

T-cell deficiency

Variable loss of cell-mediated immunity

Slide 40 · Thymus and parathyroid defects cluster together

Thymic hypoplasia or absence reduces T-cell maturation.

Parathyroid developmental defects may produce hypocalcemic tetany.

Congenital cardiovascular and craniofacial abnormalities may coexist.

The combined phenotype is a developmental syndrome, not an isolated immune mutation.

Slide 41 · 22q11 deletion connects TBX1 to developmental anatomy

22q11 region affected

A germline deletion is described in most classic cases

TBX1 dosage altered

Branchial arch and great-vessel development disrupted

Multisystem phenotype

Thymic, parathyroid and cardiovascular features

Slide 42 · DiGeorge: Immune phenotype versus tissue localization

Immune effect

Low numbers of T lymphocytes

Defective defense against some viral and fungal pathogens

Ig concentration varies with helper function

Morphologic correlate

Thymus underdeveloped or absent

Lymph-node paracortex depleted

Splenic periarteriolar T-cell sheath depleted

Slide 43 · DiGeorge T-cell deficiency varies in severity

The thymic developmental defect can range from partial to profound.

Immunoglobulin levels may be normal or depressed depending on T-cell support.

Some improvement with age in patients who retain thymic tissue.

Slide 44 · MHC class II deficiency blocks CD4⁺ T-cell development

MHC II expression lost

Defective transcriptional regulation of MHC class II genes

CD4⁺ T-cell development impaired

Antigen recognition and helper function fail

Combined immunodeficiency

Both cellular responses and B-cell help are reduced

Slide 45 · Developmental immune defects: Distinguishing clue

Disorder

Level of block

Teaching discriminator

DiGeorge syndrome

Thymic organ development

Multisystem congenital anomalies

MHC class II deficiency

MHC II expression

Deficient CD4⁺ T-cell maturation / activation

BTK deficiency

Pre-BCR signal

Very few mature B cells

RAG-associated SCID

Receptor rearrangement

Failure of both TCR and Ig assembly

Slide 46 · Class-switch recombination requires helper T-cell signals

Activated CD4⁺ T cell

CD40L / CD154 expressed

B-cell CD40 engaged

Help for immunoglobulin switching

Diversified response

Production of switched IgG, IgA and IgE

Slide 47 · Hyper-IgM syndrome retains IgM but loses switched isotypes

CD40L, CD40 or AID defective

Class switching / affinity maturation impaired

B cells remain present

Cell counts may appear normal

Serum pattern

IgM normal or raised; IgG, IgA and IgE low

Slide 48 · Hyper-IgM: T-cell help failure or intrinsic B-cell defect

CD40L or CD40 defect

Disrupts T–B interaction

Ig class switching impaired

Macrophage activation also reduced

AID defect

DNA-editing enzyme intrinsic to B cells

Class switching and affinity maturation impaired

Helper receptor interaction is not the primary lesion

Slide 49 · Hyper-IgM infections reflect low high-affinity IgG

Recurrent pyogenic infections result from deficient opsonizing IgG.

Affinity maturation is also impaired, limiting high-affinity antibody generation.

Normal peripheral B-cell numbers do not exclude this substantial functional defect.

Slide 50 · CD40L–CD40 also activates macrophages

Antigen-activated T cell

CD40L normally engages macrophage CD40

Macrophage activation

Enhanced microbicidal capacity

CD40L / CD40 absent

Increased susceptibility to Pneumocystis infection

Slide 51 · Hyper-IgM can have noninfectious manifestations

IgM antibodies occasionally react with blood cells, causing autoimmune cytopenias.

Described findings include hemolytic anemia, thrombocytopenia and neutropenia.

Older patients may develop IgM-producing plasma-cell accumulations in gastrointestinal mucosa.

Slide 52 · Ig profiles distinguish two antibody-production blocks

Feature

Agammaglobulinemia

Hyper-IgM syndrome

B-cell presence

Mature B cells few or absent

Mature B cells present

IgM

Low

Normal or elevated

IgG / IgA / IgE

Low

Very low / absent

Pathway

Early B-cell maturation

Class switch and affinity maturation

Slide 53 · CVID is a heterogeneous hypogammaglobulinemic syndrome

Common variable immunodeficiency (CVID) includes familial and sporadic presentations.

Immunoglobulins are reduced across classes, although the pattern can preferentially involve IgG.

The textbook frames the diagnosis around exclusion of defined alternative causes.

No single molecular lesion defines all cases.

Slide 54 · CVID: Mature B cells fail terminal differentiation

B cells circulate

Numbers are often normal or near normal

Plasma-cell generation fails

Activation / differentiation is insufficient

Antibody output falls

Hypogammaglobulinemia develops

Slide 55 · CVID illustrates both B-cell and helper-cell defects

B-cell survival / differentiation

BAFF receptor-related defects are examples

Plasma-cell differentiation may be impaired

Pathways are genetically heterogeneous

T-cell help / Tfh regulation

ICOS is an illustrative molecular defect

ICOS participates in Tfh development

Tfh-dependent B-cell activation may fail

Slide 56 · CVID infections resemble other antibody deficiencies

Recurrent sinopulmonary pyogenic infection is a hallmark.

The source also describes herpesvirus recurrences and serious enterovirus disease.

Persistent Giardia-associated diarrhea is another important manifestation.

The typical onset is later than X-linked agammaglobulinemia.

Slide 57 · CVID can have enlarged germinal centers but few plasma cells

B lymphocytes respond

Antigen-driven follicular proliferation persists

Germinal centers enlarge

Hyperplastic follicular architecture appears

Terminal differentiation fails

Plasma-cell formation remains inadequate

Slide 58 · CVID includes autoimmunity and malignancy risk

Autoimmune disease is an established association; Rheumatoid arthritis is a textbook example.

Lymphoid malignancies occur more frequently in affected individuals.

The source also reports an increased occurrence of gastric cancer.

Immune dysregulation therefore extends beyond recurrent infection.

Slide 59 · BTK deficiency versus CVID: Tissue-level distinction

Feature

X-linked agammaglobulinemia

CVID

Age pattern

Often evident after maternal Ig wanes

Usually later in childhood / adolescence

Blood B cells

Markedly reduced

Often retained

Germinal centers

Underdeveloped

May be hyperplastic

Plasma cells

Absent

Insufficiently generated

Slide 60 · Selective IgA deficiency weakens mucosal surveillance

Differentiation defect

Insufficient IgA-producing plasma cells

IgA level falls

Serum and secretory IgA markedly reduced

Mucosal protection falls

Respiratory / intestinal / urogenital vulnerability

Slide 61 · IgA deficiency has a broad clinical spectrum

Many affected individuals have no symptoms.

Symptomatic individuals may have recurrent sinopulmonary infection or diarrhea.

Respiratory allergy and autoimmune disorders are more frequent in this group.

The molecular basis remains unexplained in many patients.

Slide 62 · Transfusion reactions are a clinically relevant IgA caveat

Some IgA-deficient patients can react severely when exposed to donor IgA.

The possibility of life-threatening anaphylaxis.

This is a risk in a subset of patients, not an inevitable outcome of IgA deficiency.

Slide 63 · Antibody syndromes: Dominant defect at a glance

Disorder

Primary abnormality

Typical clue

X-linked agammaglobulinemia

Mature B-cell deficiency

Early pyogenic infections

Hyper-IgM syndrome

Immunoglobulin class-switch failure

IgM retained; switched isotypes deficient

CVID

Plasma-cell differentiation / help

Low Ig; B cells often present

Selective IgA deficiency

IgA secretion impaired

Asymptomatic or mucosal infection

Slide 64 · XLP impairs cellular control of EBV-infected B cells

SAP adaptor defective

SLAM-family immunoreceptor signaling disrupted

NK / T-cell responses weakened

Control of EBV-infected cells is impaired

Severe EBV phenotype

Fulminant mononucleosis and B-cell proliferation

Slide 65 · SAP also supports T follicular helper cell development

SAP dysfunction

Impaired Tfh development

Germinal-center defect

Insufficient organized B-cell maturation

Low antibody quality

Poor high-affinity antibody generation

Slide 66 · XLP is unusually selective for severe EBV disease

The source emphasizes extreme susceptibility to Epstein–Barr virus.

Fulminant infectious mononucleosis and B-cell tumors are characteristic outcomes.

The reason for relative selectivity compared with other viral infections is uncertain.

Slide 67 · Other activation defects can impair Th17 defense

Lymphocyte activation requires intact receptor-associated biochemical pathways.

Impaired Th17 responses are associated in the source with mucocutaneous candidiasis.

The textbook also describes bacterial skin infections in the associated clinical phenotype.

Slide 68 · Primary immune regulatory disorders cause dysregulated immunity

PIRDs arise when molecular circuits that restrain or coordinate immune responses fail.

The resulting phenotype can combine autoimmunity, infections and lymphoproliferation.

Some syndromes also carry a malignancy risk.

Immune activation can be excessive even when host defense is ineffective.

Slide 69 · Gain-of-function signaling can amplify cytokine responses

STAT1 / STAT3 / JAK1 GOF

The source gives these as PIRD examples

Signaling tone increased

Cytokine downstream activity amplified

Immune dysregulation

Autoimmune / infectious manifestations coexist

Slide 70 · CTLA-4 insufficiency weakens inhibitory signaling

CTLA-4 dosage reduced

A negative regulatory checkpoint is weakened

Activation threshold shifts

Normal immune inhibition is insufficient

Dysregulated responses

Early autoimmunity and lymphoproliferation may emerge

Slide 71 · Activated PI3Kδ syndrome increases pro-activation signals

PI3Kδ pathway overactive

Positive signaling is amplified

Immune balance changes

Baseline lymphocyte activation is altered

PIRD phenotype

Infection and immune dysregulation may coexist

Slide 72 · Regulatory T-cell defects damage immune tolerance

FOXP3 / STAT5B defect

Treg differentiation or function impaired

Tolerance impaired

Self-reactive responses are less restrained

Early autoimmunity

Immune-mediated tissue injury can dominate

Slide 73 · PIRD mechanisms share a dysregulation endpoint

Mechanism

Source examples

Principal functional change

Excess cytokine signal

STAT1, STAT3, JAK1 GOF

Hyperactive signaling

Reduced inhibitory checkpoint

CTLA-4 haploinsufficiency

Insufficient restraint

Amplified activation

Activated PI3Kδ syndrome

Increased positive signaling

Failed regulatory tolerance

FOXP3, STAT5B deficiencies

Impaired Treg control

Slide 74 · Targeted therapy is pathway-dependent in PIRDs

JAK inhibitors as an example in certain STAT gain-of-function syndromes.

Such pathway-directed treatments do not generalize to every PIRD.

The excerpt does not provide gene-specific treatment algorithms or outcomes.

Management details beyond these statements require separate guideline review.

Slide 75 · One pathway map connects major adaptive deficiencies

Maturation

γ-chain, ADA, RAG, BTK, thymic organogenesis

Activation / help

MHC II, CD40L–CD40, AID, ICOS

Regulation / control

SAP, CTLA-4, PI3Kδ, FOXP3

Slide 76 · Immune readouts guide differential diagnosis

Typical finding

Most informative diagnostic direction

T cells profoundly reduced + opportunistic infections

SCID / severe T-cell development defect

Mature B cells profoundly reduced + low all Ig

BTK-related agammaglobulinemia

Normal B counts + IgM retained / switched Ig low

Hyper-IgM syndrome

B counts often normal + broad hypogammaglobulinemia

CVID

Marked IgA reduction + mucosal infections

Selective IgA deficiency

Slide 77 · Clinical reasoning: Repeated pyogenic respiratory infections

Illustrative vignette

A male infant develops otitis, sinusitis and pneumonia after the first months of life; Mature blood B cells are nearly absent.

Which maturation checkpoint best explains this pattern?

Interpretation: BTK-dependent pre-B receptor signaling is defective in classic X-linked agammaglobulinemia.

Slide 78 · Clinical reasoning: IgM is retained but IgG is very low

Illustrative vignette

A child has recurrent pyogenic infection with circulating B cells and normal-to-raised IgM, but marked loss of switched immunoglobulins.

Which immune interaction or enzyme should be evaluated?

Interpretation: Consider class-switch pathway defects involving CD40L, CD40 or AID.

Slide 79 · Clinical reasoning: Severe EBV infection

Illustrative vignette

A boy develops unusually severe infectious mononucleosis and B-cell lymphoproliferation after EBV infection.

Which adaptive immune signaling disorder is characteristic?

Interpretation: SAP-related X-linked lymphoproliferative disease impairs NK/T-cell antiviral control.

Slide 80 · Clinical clues separate immune deficiency from dysregulation

Deficient effector capacity

Severe or recurrent pathogen-specific infections

Low mature lymphocyte numbers or antibody output

Tissue hypoplasia may parallel absent lineage

Dysregulated activation / tolerance

Early autoimmunity and lymphoproliferation

Mutations alter activation or inhibitory balance

Infection susceptibility may coexist

Slide 81 · Core diagnostic logic from the chapter

First identify the failing compartment: T cells, mature B cells, secreted antibody or regulation.

Then localize the failed checkpoint: Development, antigen-receptor signaling, T-cell help or tolerance.

Interpret infections and lymphoid morphology together; Neither alone specifies the genotype.

The source provides mechanistic syndromes, not a complete modern laboratory-testing algorithm.

Slide 82 · Summary: Developmental blocks versus late functional defects

SCID, DiGeorge syndrome and BTK deficiency primarily disrupt immune-cell development.

Hyper-IgM syndrome and CVID chiefly impair effective antibody diversification or differentiation.

SAP defects threaten EBV control; PIRDs disturb activation and tolerance.

Clinical phenotype follows which defensive task has been lost or misregulated.

Slide 83 · Primary source

Robbins, Cotran & Kumar

Pathologic Basis of Disease

11th edition (2026)

Chapter section: Defects in Adaptive Immunity