Immunodeficiencies Associated With Systemic Diseases

Slide 1 · Immunodeficiencies Associated

With Systemic Diseases

Inherited multisystem syndromes and secondary immune deficiency

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning goals

Identify the systemic features and immune defects of Wiskott–Aldrich syndrome.

Connect ATM-dependent DNA damage responses to the phenotype of ataxia-telangiectasia.

Distinguish inherited multisystem immunodeficiency from acquired immune suppression.

Relate the major acquired causes to their dominant mechanisms.

Slide 3 · Two routes to immune dysfunction

Inherited systemic disorder

A germline defect affects immunity and other organs

Acquired systemic condition

Disease, treatment, or organ loss interferes with immunity

Both routes can produce infection susceptibility, but their initiating lesions differ.

Slide 4 · Why “systemic” matters

In the inherited syndromes, immune deficiency coexists with conspicuous nonimmune findings.

The combination of infection susceptibility and a multisystem phenotype guides recognition.

In acquired deficiency, the systemic disease or exposure often precedes immune dysfunction.

An abnormal antibody profile does not fully describe tissue and cellular immunity.

Slide 5 · Immune compartments implicated

T lymphocytes

Progressive depletion or impaired T-cell function may reduce cellular immunity.

B-cell responses

Antigen-specific responses and isotype-switched antibody production may be impaired.

Marrow leukopoiesis

Cancer or cytotoxic treatments may reduce leukocyte production.

Splenic clearance

Loss of the spleen decreases phagocytosis of blood-borne microbes.

Slide 6 · Inherited versus secondary deficiency

Inherited syndromes

Initiating cause: A gene defect.

Wiskott–Aldrich and ataxia-telangiectasia are the two systemic examples in the source.

Immune and extraimmune findings coexist.

Secondary deficiency

Initiating context: Systemic illness, treatment, nutritional deficit, chronic infection, or splenic removal.

The mechanisms include decreased production, function, or clearance.

Slide 7 · Read the phenotype from the mechanism

Initiating lesion

WASP pathway, ATM pathway, or acquired insult

Immune consequence

T-cell loss, impaired antibodies, leukopenia, or clearance defect

Clinical expression

Recurrent infection ± distinctive systemic findings

The same endpoint—susceptibility to infection—can arise through different mechanisms.

Slide 8 · What the textbook does—and does not—specify

Robbins gives two inherited multisystem examples: Wiskott–Aldrich and ataxia-telangiectasia.

It groups a broad set of secondary causes and summarizes selected mechanisms.

The supplied section does not give complete diagnostic algorithms or quantitative test thresholds.

AIDS receives its own subsequent section; Here, it is retained as a cause of secondary deficiency.

Slide 9 · Wiskott–Aldrich: Clinical triad

Thrombocytopenia

A platelet abnormality is part of the defining syndrome.

Eczema

Cutaneous disease is a prominent extraimmune manifestation.

Recurrent infections

Marked vulnerability reflects associated immune dysfunction.

Slide 10 · The WAS triad signals one inherited syndrome

Thrombocytopenia

Hematologic

Eczema

Cutaneous

Susceptibility to infection

Immune

Three coexisting findings—not one isolated immunoglobulin abnormality.

Slide 11 · Inheritance and molecular location

Wiskott–Aldrich syndrome is X-linked.

The causal gene lies at chromosome Xp11.23.

It encodes Wiskott–Aldrich syndrome protein (WASP).

The named protein links a genetic defect to immune-cell cytoskeletal function.

Slide 12 · WASP: Receptor-to-cytoskeleton linkage

Membrane receptors

Antigen receptors are one example

WASP

Proposed coupling between receptors and cytoskeletal elements

Cytoskeletal responses

Cell migration and signal transduction may be affected

Mechanism is phrased as proposed rather than established for each cellular response.

Slide 13 · Mechanistic caution: What is established?

The disease is associated with mutations in the gene encoding WASP.

WASP belongs to a protein family believed to link surface receptors to cytoskeletal elements.

The source proposes roles in migration and signal transduction.

Do not read the schematic as a fully demonstrated, single-pathway account of all clinical findings.

Slide 14 · T-cell compartment changes over time

Early course

Thymus can look morphologically normal

Later course

Progressive loss of circulating T lymphocytes

Lymph-node findings

Fewer T cells in paracortical zones

Normal early thymic morphology does not exclude evolving peripheral dysfunction.

Slide 15 · WAS: Progressive depletion of paracortical T cells

Earlier in disease

Paracortex

T-cell zone present

Later in disease

Paracortex

Reduced paracortical T cells

Conceptual lymph-node sections — not H&E microscopy

Slide 16 · Functional cellular immunity is variable

Progressive peripheral T-cell loss is a characteristic finding.

The accompanying impairment of cellular immunity varies among patients.

The T-cell compartment cannot be inferred solely from initial thymic morphology.

Lymph-node paracortical depletion is a tissue correlate of the systemic T-cell abnormality.

Slide 17 · Antibody responses: Antigen matters

Polysaccharide antigens

Patients fail to make antibodies to these antigens.

Protein antigens

Antibody responses are poor rather than wholly absent.

Serum IgG

Usually normal in concentration despite defective antigen-specific responses.

Slide 18 · Normal IgG does not ensure effective responses

Serum measurement

IgG concentration can be normal

Functional measurement

Specific responses to antigens are abnormal

Clinical inference

A normal single class level does not exclude immune deficiency

Concentration and functional responsiveness answer different questions.

Slide 19 · Characteristic immunoglobulin profile

IgM

Typically decreased in serum.

IgG

Usually within the normal range.

IgA / IgE

Often elevated, despite impaired responses to other antigens.

Slide 20 · The WAS immune phenotype is mixed

Cellular compartment: Progressive T-lymphocyte depletion.

Humoral compartment: Abnormal antigen-specific antibody production.

Serum immunoglobulins: A nonuniform pattern across classes.

Combined functional defects help explain susceptibility to repeated infections.

Slide 21 · Clinical interpretation of recurrent infection

Recurrent infections

Recognize a defining syndrome component

Extraimmune clues

Look for eczema and thrombocytopenia

Immune pattern

Review T-cell and humoral abnormalities together

The cluster is more distinctive than infection alone.

Slide 22 · WAS: Lymphoma susceptibility

Increased susceptibility to B-cell lymphomas.

Infection vulnerability and malignancy risk coexist in this inherited condition.

Lymphoma association is distinct from the characteristic presenting triad.

The supplied section does not quantify the risk or specify lymphoma subtypes.

Slide 23 · WAS: Molecular lesion to major manifestations

WASP gene mutation

X-linked, Xp11.23

Immune-cell abnormalities

T-cell depletion and dysfunctional antibody responses

Clinical outcomes

Infection susceptibility; Systemic triad; Lymphoma predisposition

Concept map—does not imply every manifestation has a single established intermediate.

Slide 24 · WAS: Therapeutic statement

The supplied text names hematopoietic stem-cell (HSC) transplantation as treatment.

This is a statement from the specified textbook section.

No transplant indications, outcomes, or alternative treatment regimen is detailed here.

Clinical management recommendations require sources beyond this excerpt.

Slide 25 · Case application: Wiskott–Aldrich

A young male patient has recurrent infections, eczematous skin disease, and thrombocytopenia. Immunologic testing shows low serum IgM; IgG is not reduced.

Clinical reasoning

Which inherited syndrome unites the findings?

Why does normal total IgG not dismiss dysfunction?

Slide 26 · Reasoning through the WAS case

Syndrome match

The constellation of eczema, thrombocytopenia, and infection supports Wiskott–Aldrich.

Humoral finding

IgG can be normal while antibody response to polysaccharide and protein antigens is defective.

Cellular context

Progressive T-cell loss and variable cellular immune impairment may coexist.

Slide 27 · Ataxia-telangiectasia: Multisystem phenotype

Neurologic

Abnormal gait (ataxia) and other neurologic deficits.

Vascular

Telangiectases are characteristic vascular malformations.

Immune

Variable B-cell and T-cell abnormalities with recurrent infection.

Neoplastic

Increased incidence of tumors, including lymphoma.

Slide 28 · Inheritance and gene product

Ataxia-telangiectasia is autosomal recessive.

The causal gene is located on chromosome 11.

It encodes ATM: Ataxia telangiectasia mutated protein kinase.

ATM participates in the response to DNA double-strand breaks.

Slide 29 · ATM is activated in response to DNA damage

DNA double-strand break

A signal of DNA damage

ATM protein kinase

Phosphorylates p53

P53-mediated response

Checkpoint activation and/or apoptosis

The p53 response follows DNA damage; Outcome depends on the cell context.

Slide 30 · Cell-cycle checkpoints protect damaged cells

ATM-dependent phosphorylation activates p53 after double-strand breaks.

P53 can initiate checkpoint responses in cells containing damaged DNA.

P53 can also activate apoptosis under appropriate circumstances.

Deficient ATM disrupts this DNA-damage response axis.

Slide 31 · Antigen-receptor recombination also uses DNA breaks

V(D)J recombination

DNA segments recombine during antigen-receptor generation

Double-strand break complexes

ATM helps maintain their stability

ATM deficiency

May impair production of diverse antigen receptors

This is a potential route from DNA repair defect to impaired lymphocyte function.

Slide 32 · ATM deficiency: Two immunologic routes

Antigen-receptor generation

Abnormal DNA break processing may compromise V(D)J recombination.

Antibody class switching

Defective DNA recombination may impair isotype switching.

DNA-damage surveillance

Abnormal checkpoint/apoptotic signaling accompanies repair defects.

Slide 33 · Immunoglobulin isotype switching in A–T

DNA recombination

Required for change in antibody isotype

ATM-dependent integrity

DNA break processing is disrupted in deficiency

Humoral consequence

Production of switched isotypes is defective

The strongest stated abnormalities involve IgA and IgG2.

Slide 34 · A–T: Principal humoral abnormalities

Defective production of isotype-switched antibodies is prominent.

IgA and the IgG2 subclass.

The severity of B-cell dysfunction differs among affected individuals.

This pattern is distinct from the characteristic serum immunoglobulin changes in Wiskott–Aldrich syndrome.

Slide 35 · A–T: T-cell abnormalities

T-cell defects may occur, but are usually less prominent than the humoral defects.

The source associates T-cell defects with thymic hypoplasia.

B-cell and T-cell involvement may vary in severity.

An isolated antibody assessment may not describe the full defect.

Slide 36 · Distinct tissue features in the two syndromes

Wiskott–Aldrich

Thymus may be morphologically normal initially

Ataxia-telangiectasia

T-cell defects are associated with thymic hypoplasia

A normal thymus early in WAS is not equivalent to thymic hypoplasia reported in A–T.

Slide 37 · A–T: Infection phenotype

Patients are vulnerable to bacterial infections in the upper respiratory tract.

Lower respiratory tract bacterial infections also occur.

The text describes combined immune abnormalities with variable severity.

The infection pattern must be interpreted alongside neurologic and vascular findings.

Slide 38 · A–T: Consequences beyond infection

Autoimmunity

Multiple autoimmune phenomena occur.

Neoplasia

Cancers become increasingly frequent with advancing age.

Lymphoma

A markedly increased incidence.

Slide 39 · ATM deficiency: Immune and neoplastic associations

ATM deficiency

Abnormal response to double-strand DNA damage

Immune effects

Potential recombination and isotype-switching defects

Cancer association

Increased occurrence of malignancy, especially lymphoma

Shared molecular context helps integrate immune deficiency and malignancy.

Slide 40 · A–T: Certainty of molecular statements

ATM-mediated phosphorylation of p53 is described directly.

ATM also contributes to stability of DNA-break complexes during V(D)J recombination.

Effects on antigen-receptor generation are presented as possible.

Disordered class switching is linked to defective DNA repair as a proposed mechanism.

Slide 41 · Case application: Ataxia-telangiectasia

A child has abnormal gait, telangiectases, and recurrent bacterial respiratory infections. Studies indicate poor production of IgA and IgG2.

Clinical reasoning

Which syndrome best integrates the abnormalities?

Which DNA-damage-response protein is affected?

Slide 42 · Reasoning through the A–T case

Syndrome

Ataxia and telangiectases distinguish the phenotype from a generic immunodeficiency.

Immunology

Impaired isotype-switched antibody production matches the IgA / IgG2 pattern.

Pathogenesis

ATM dysfunction links DNA-damage signaling with immune recombination problems.

Slide 43 · Wiskott–Aldrich versus ataxia-telangiectasia

Feature

Wiskott–Aldrich

Ataxia-telangiectasia

Inheritance

X-linked

Autosomal recessive

Core gene product

WASP

ATM protein kinase

Extraimmune clues

Eczema; Thrombocytopenia

Ataxia; Telangiectases

Typical immune pattern

T-cell decline; Poor antibody responses

IgA / IgG2 switching defects

Neoplasia

B-cell lymphoma risk

Lymphoma; Other cancers

Slide 44 · Two molecular bottlenecks

WASP

Membrane-receptor/cytoskeletal linkage and cell responses.

ATM

Double-strand-break response, DNA recombination, and class switching.

Shared outcome

Immune defects plus increased lymphoma susceptibility, via distinct mechanisms.

Slide 45 · Secondary immunodeficiencies are more common

Secondary (acquired) immunodeficiency arises in the setting of systemic conditions or exposures.

These collectively outnumber primary genetic immunodeficiency disorders.

Possible initiating events include underlying disease, therapeutic intervention, or organ removal.

The resulting deficit may involve immune-cell production, immunoglobulin synthesis, cell survival, or microbial clearance.

Slide 46 · Systemic settings associated with acquired deficiency

Systemic illnesses

Cancer, diabetes/other metabolic disorders, chronic infection, aging.

Nutritional status

Protein-calorie malnutrition.

Therapeutic exposure

Cancer chemotherapy or irradiation; Immunosuppressive medications.

Anatomic loss

Removal of the spleen.

Slide 47 · Acquired deficiency: Four dominant mechanisms

Reduced production

Marrow infiltration; Chemotherapy; Radiation

Impaired function

Malnutrition-linked lymphocyte dysfunction

Cell loss

Drug- or infection-associated depletion

Reduced clearance

Splenic removal

Different initiating conditions may converge on similar susceptibility to infection.

Slide 48 · Cancer can compromise the bone marrow

Leukemias may involve the marrow, interfering with normal leukocyte production.

Metastatic cancer can likewise occupy marrow and reduce production.

Reduced immune-cell output is a recognized route to secondary deficiency.

This mechanism is different from an inherited lymphocyte-signaling defect.

Slide 49 · Marrow involvement: Effect on host defense

Leukemia or metastasis

Bone marrow involvement

Hematopoiesis

Lower leukocyte production

Immune defense

Acquired vulnerability due to fewer cells

A production deficit is an acquired quantitative mechanism.

Slide 50 · Chemotherapy: An iatrogenic mechanism

Cancer-directed chemotherapy is a listed cause of secondary immunodeficiency.

One key mechanism is reduced leukocyte production.

Treatment exposure may generate immune dysfunction in addition to the underlying malignancy.

The textbook excerpt does not supply drug-specific risk or recovery timelines.

Slide 51 · Radiation therapy and leukocyte production

Ionizing radiation treatment

Can damage hematopoietic marrow

Reduced leukocyte production

Fewer cells available for host defense

Secondary immune deficiency

Therapy-related vulnerability

Radiation and chemotherapy appear together Table 6.13.

Slide 52 · Protein-calorie malnutrition

Systemic context

Insufficient nutrition is a listed acquired cause.

Mechanism

Metabolic derangements inhibit lymphocyte maturation and function.

Antibody production

The narrative also describes inadequate immunoglobulin synthesis.

Interpretation

Nutritional state may impair more than one arm of immune defense.

Slide 53 · Malnutrition can disrupt multiple immune functions

Protein-calorie malnutrition

Metabolic derangement

Lymphocyte compartment

Maturation and function inhibited

Humoral response

Immunoglobulin synthesis may be inadequate

Effects on lymphocytes and Ig production are both source-described.

Slide 54 · Loss of the spleen: A clearance defect

Splenic removal is specifically listed in Table 6.13.

The table identifies decreased phagocytosis of blood-borne microbes as the mechanism.

Unlike chemotherapy-related deficiency, the primary defect described is not reduced marrow output.

This illustrates an acquired defect of a host-defense organ.

Slide 55 · Spleen removal changes microbial handling

Spleen present

Contributes to phagocytosis of blood-borne microbes

Splenectomy

Anatomic loss of this phagocytic function

Outcome

Reduced clearance in the bloodstream

This is not a depiction of a specific pathogen or infection risk estimate.

Slide 56 · HIV: Lymphocyte depletion as a prototype

HIV infection is one cause Table 6.13.

Its listed immune mechanism is depletion of CD4-positive helper T cells.

The following AIDS section describes profound immunosuppression and opportunistic disease.

HIV pathogenesis and clinical AIDS are developed in separate Robbins teaching units.

Slide 57 · Additional acquired contexts named by Robbins

Diabetes / metabolic disease

Associated with secondary immune deficiency; No specific mechanism detailed here.

Aging

Recognized as a context, without an age-specific mechanism in this excerpt.

Chronic infection

Can be associated with lymphocyte depletion during severe infection.

Immunosuppressive drugs

Given for graft rejection prevention or autoimmune disorders; Depletion may occur.

Slide 58 · Drugs and severe infection can deplete lymphocytes

Initiating insult

Immunosuppressive drug or severe infection

Immune compartment

Lymphocyte depletion

Consequence

An acquired deficit of lymphocyte-mediated defenses

The effect is broadly described; No specific drug class or pathogen is inferred.

Slide 59 · Robbins Table 6.13: Cause–mechanism map

Cause

Listed mechanism

HIV infection

CD4 helper-T-cell depletion

Chemotherapy / irradiation

Reduced leukocyte production

Cancer involving marrow

Reduced leukocyte production

Protein-calorie malnutrition

Inhibited lymphocyte maturation and function

Splenectomy

Reduced phagocytosis of blood-borne microbes

Slide 60 · Mechanism-first clinical discrimination

Production defect

Ask whether cytotoxic therapy or tumor infiltration affects marrow.

Functional defect

Consider malnutrition and abnormal lymphocyte performance.

Cell-depletion defect

Consider drugs or severe infection; HIV specifically targets CD4 helper T cells.

Clearance defect

Ask whether the spleen is absent.

Slide 61 · Case: Immunodeficiency after cancer therapy

A person receiving cancer chemotherapy develops evidence of reduced leukocyte production and increased susceptibility to infections.

Clinical reasoning

Is the initiating cause inherited or acquired?

Which mechanism does the Robbins table identify?

Slide 62 · Case interpretation: Cancer therapy

Classification

Secondary (treatment-associated) immunodeficiency.

Mechanism

Chemotherapy can suppress leukocyte production.

Distinction

This differs from WASP- or ATM-associated genetic immune syndromes.

Slide 63 · Case: A clearance rather than production problem

A person without a spleen is being assessed for predisposition to infection. There is no statement that marrow leukocyte production has fallen.

Clinical reasoning

What host-defense function is explicitly impaired by splenectomy?

Why is a marrow-production model insufficient?

Slide 64 · Case interpretation: Splenectomy

Primary deficit

Less phagocytosis of blood-borne microbes.

Mechanistic category

Loss of an organ-dependent microbial clearance function.

Contrast

Chemotherapy and marrow cancer are linked to reduced leukocyte production.

Slide 65 · Genetic lesions and acquired insults converge

Inherited systemic examples

WASP-associated defect: Linked to cell signaling/cytoskeletal function.

ATM-associated defect: DNA-damage response and immune recombination.

Both have nonimmune syndromic clues.

Acquired causes

Reduced leukocyte output, inadequate immunoglobulin synthesis, lymphocyte depletion, or impaired phagocytosis.

A preceding illness, therapy, or organ loss may identify the route.

Slide 66 · Match the clue to the dominant mechanism

Clinical or contextual clue

Source-supported interpretation

Eczema + thrombocytopenia

Consider Wiskott–Aldrich

Ataxia + telangiectases

Consider ataxia-telangiectasia

Cancer occupying marrow

Reduced leukocyte production

Protein-calorie malnutrition

Lymphocyte maturation/function impaired

History of splenectomy

Reduced phagocytosis of blood-borne microbes

Slide 67 · Interpretations to avoid

Do not treat a normal total IgG level as proof of normal antigen-specific immunity in WAS.

Do not assume that all A–T immune defects are strictly humoral: T-cell abnormalities may occur.

Do not equate every acquired deficiency with low leukocyte production; Splenectomy is a clearance defect.

Do not expand the brief HIV table entry into a full AIDS lecture within this topic.

Slide 68 · Clinical reasoning: Phenotype → mechanism

Recognize context

Syndromic triad, neurologic signs, illness, therapy, or organ loss

Identify immune compartment

T cells, antibody function, production, or phagocytosis

State supported conclusion

Link to the specific mechanism

Avoid overextending the source into unverified tests or management algorithms.

Slide 69 · Synthesis: Four distinctions worth retaining

WAS: X-linked WASP defect; Thrombocytopenia, eczema, infections; T-cell loss and abnormal antibody responses.

A–T: Recessive ATM defect; Ataxia, telangiectases, impaired switched antibodies, lymphoma risk.

Secondary disorders are common and are usually recognized in a relevant systemic or treatment context.

The dominant immune mechanism differs substantially across acquired causes.

Slide 70 · Reference and source boundary

Primary text

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026).

Direct section

Chapter 6, “Immunodeficiencies Associated With Systemic Diseases,” p. 218.

Grouped subsection

“Secondary Immunodeficiencies,” pp. 218–219, including Table 6.13.

Evidence limitation

Source Markdown available; original PDF pages and photographic figures were not supplied.