Defects in Innate Immunity

Slide 1 · Defects in Innate Immunity

Inherited dysfunction of leukocytes and complement

Clinicopathologic mechanisms and disease patterns

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Locate the functional lesion in major inherited leukocyte disorders.

Relate receptor, trafficking, and oxidative defects to infectious phenotypes.

Explain how complement-component and regulatory deficiencies produce distinct disease patterns.

Use a mechanism-first differential for representative clinical presentations.

Slide 3 · Two principal classes of innate defects

Leukocyte function

Adhesion and migration

Phagolysosomal traffic

Microbicidal activity

Innate receptor/cytokine signaling

Complement system

Initiation or amplification

Central C3 effector function

Terminal membrane attack

Restraint of activation

Slide 4 · Innate defenses: Cellular and humoral arms

Cellular defenses

Neutrophils and macrophages

Recognition, ingestion, and killing

Leukocyte recruitment to tissues

Humoral defenses

Complement proteins in plasma

Opsonization and inflammation

Terminal lysis of susceptible microbes

Slide 5 · The critical checkpoints in pathogen clearance

Sense microbial threat

Recruit leukocytes

Engulf microbe

Deliver granule contents

Kill and contain

Functional sequence — schematic

Slide 6 · Leukocyte exit from blood requires ordered steps

Margination

Rolling

Firm adhesion

Transmigration

Tissue chemotaxis

Functional sequence — schematic

Slide 7 · Leukocyte adhesion deficiency type 1

Defective β2 integrin chain shared by LFA-1 and Mac-1.

Impairs firm leukocyte adhesion to activated endothelium.

Migration to infected tissue is consequently reduced.

Normal: β2 integrin engagement

LAD-1: Adhesion failure

Outcome: Impaired tissue entry

Schematic

Slide 8 · LAD-1 disrupts the firm-adhesion checkpoint

β2-integrin defect

Weak stable attachment

Poor transendothelial migration

Reduced neutrophils at infection site

Causal sequence — schematic

Slide 9 · Why circulating phagocytes cannot compensate

Microbial killing requires phagocytes to reach the infected tissue.

The adhesion defect acts upstream of ingestion and killing.

Even intact intracellular killing is ineffective if cells cannot localize to the focus.

LAD-1 to recurrent, potentially severe bacterial infections.

Slide 10 · Leukocyte adhesion deficiency type 2

A fucosyltransferase mutation impairs synthesis of sialyl-Lewis X.

Sialyl-Lewis X serves as a ligand for E- and P-selectins.

Loss of this ligand weakens the early adhesion/rolling interaction.

Fucosyltransferase mutation

Absent selectin ligand

Defective early endothelial tethering

Schematic

Slide 11 · LAD-2 affects an earlier recruitment step

Defective fucosylation

Sialyl-Lewis X loss

Ineffective selectin binding

Poor leukocyte recruitment

Causal sequence — schematic

Slide 12 · LAD-1 versus LAD-2: Same endpoint, different lesion

Feature

LAD-1

LAD-2

Primary lesion

β2 integrin common chain

Fucosyltransferase

Adhesion component

LFA-1 / Mac-1

Sialyl-Lewis X

Predominant checkpoint

Firm adhesion

Selectin-mediated tethering / rolling

Consequence

Defective leukocyte tissue entry

Defective leukocyte tissue entry

Slide 13 · Application: Recurrent bacterial infection and failed adhesion

ILLUSTRATIVE TEACHING VIGNETTE

Teaching vignette: A child has repeated severe bacterial infections. Phagocytic cells are present in the circulation, but migration from blood into affected tissue is inefficient.

Question: Which functional checkpoint has failed?

Mechanistic answer: Endothelial adhesion / tissue recruitment; Molecular distinction requires evaluating integrin versus selectin-ligand function.

Slide 14 · Phagocytosis proceeds through linked compartments

Microbial recognition

Engulfment

Phagosome formation

Fusion with lysosome

Intracellular degradation

Functional sequence — schematic

Slide 15 · Chédiak–Higashi syndrome: Molecular basis

Autosomal recessive disorder involving the LYST gene.

LYST encodes a regulator implicated in lysosomal trafficking.

Abnormal intracellular granule handling compromises phagocyte function.

LYST dysfunction

Disturbed granule traffic

Defective antimicrobial action

Schematic

Slide 16 · Phagolysosomal fusion is functionally impaired

Abnormal lysosomal trafficking

Phagosome–lysosome fusion defect

Defective degranulation

Delayed microbial killing

Causal sequence — schematic

Slide 17 · Giant leukocyte granules: A morphologic clue

Abnormally large cytoplasmic granules visible on peripheral-blood smears.

Usual granule distribution

Chédiak–Higashi: Giant granules

Slide 18 · Chédiak–Higashi impairs multiple phagocyte tasks

Neutropenia decreases available circulating neutrophils.

Defective degranulation disrupts antimicrobial delivery.

Delayed microbial killing permits persistence after phagocytosis.

These abnormalities together increase susceptibility to infection.

Slide 19 · LYST dysfunction affects tissues beyond leukocytes

Melanocytes

Abnormal pigment handling

Albinism

Nervous system

Lysosomal-related cellular dysfunction

Neurologic abnormalities

Platelets

Granule-related functional abnormality

Bleeding tendency

Slide 20 · A multisystem pattern distinguishes Chédiak–Higashi

The leukocyte phenotype alone resembles other phagocyte defects.

Albinism raises suspicion for a broader intracellular-trafficking disorder.

Neurologic and bleeding manifestations localize pathology beyond neutrophils.

Giant cytoplasmic granules provide a distinctive morphologic clue.

Slide 21 · Application: Enlarged granules and infections

ILLUSTRATIVE TEACHING VIGNETTE

Teaching vignette: A child with recurrent infections also has reduced pigmentation, bleeding problems, and giant cytoplasmic granules in leukocytes.

Question: Does the principal defect involve adhesion, granule traffic, or ROS production?

Mechanistic answer: LYST-associated lysosomal trafficking / phagolysosomal function (Chédiak–Higashi syndrome).

Slide 22 · Oxygen-dependent killing follows ingestion

Microbe engulfed

Phagocyte oxidase activation

Superoxide generation

Reactive oxygen species

Microbial damage

Functional sequence — schematic

Slide 23 · Respiratory burst: The chemical purpose

The phagocyte oxidase complex uses NADPH and oxygen.

Its activity generates superoxide, a major reactive oxygen species.

The acute oxygen consumption is termed the respiratory burst.

NADPH + O₂

Phagocyte oxidase

Superoxide (O₂•⁻)

Schematic

Slide 24 · Chronic granulomatous disease is an oxidase defect

Inherited oxidase defect

Decreased superoxide burst

Insufficient oxygen-dependent killing

Persistent / recurrent infection

Causal sequence — schematic

Slide 25 · CGD includes X-linked and recessive forms

Genetic pattern

Affected oxidase element

Example protein

X-linked

Membrane-associated component

gp91phox

Autosomal recessive

Cytoplasmic component

p47phox

Autosomal recessive

Cytoplasmic component

p67phox

Slide 26 · The gp91phox-associated CGD mechanism

A membrane-bound oxidase component is defective.

Assembly/activity of the microbicidal oxidase is compromised.

The resulting oxidative burst is insufficient for normal killing.

Membrane component defect

Oxidase dysfunction

Microbial persistence

Schematic

Slide 27 · Cytoplasmic-component CGD has the same endpoint

P47phox and p67phox are cytoplasmic oxidase components.

Autosomal recessive variants involving these components.

Different molecular lesions converge on reduced oxidative microbicidal activity.

Cytoplasmic component defect

Oxidase dysfunction

Microbial persistence

Schematic

Slide 28 · CGD manifests through failed intracellular killing

Neutrophils can encounter and ingest microbes, yet oxygen-dependent killing is impaired.

Recurrent bacterial infections.

The infection phenotype reflects failure after cellular recruitment and phagocytosis.

This differs mechanistically from impaired leukocyte extravasation in LAD.

Slide 29 · Why granulomas form in CGD

Inadequate acute neutrophil killing

Microbial persistence

Chronic macrophage-rich inflammation

Granuloma formation

Causal sequence — schematic

Slide 30 · Granulomas in CGD are a secondary response

The term “granulomatous” describes the host response, not the primary molecular lesion.

Activated macrophages accumulate and attempt to contain persistent microbes.

A granuloma may wall off organisms that were not rapidly cleared.

The underlying defect remains oxidase-dependent microbicidal activity.

Slide 31 · Chédiak–Higashi versus CGD

Feature

Chédiak–Higashi

CGD

Major lesion

LYST-dependent lysosomal traffic

Phagocyte oxidase

Defective step

Granule handling/fusion

ROS generation

Distinctive clue

Giant leukocyte granules

Macrophage-rich granulomas

Additional findings

Albinism, neurologic, platelet defects

Chronic inflammatory containment

Slide 32 · Application: Persistent infection and granulomas

ILLUSTRATIVE TEACHING VIGNETTE

Teaching vignette: Recurrent bacterial infections are accompanied by macrophage-rich granulomatous inflammation despite the presence of phagocytes.

Question: Which leukocyte killing pathway should be considered?

Mechanistic answer: Impaired phagocyte oxidase–dependent superoxide generation (CGD).

Slide 33 · Pattern-recognition receptors initiate rapid defense

Microbial product

Pattern-recognition receptor

Adaptor signaling

Antimicrobial response

Causal sequence — schematic

Slide 34 · TLR3 detects viral RNA

Toll-like receptor 3 (TLR3) senses viral RNA.

Its signaling contributes to protective antiviral responses.

Inherited defects of this pathway are associated with herpes simplex encephalitis.

Viral RNA

TLR3 signaling

Antiviral response

Schematic

Slide 35 · A tissue-specific clue: Herpes simplex encephalitis

TLR3 defects with recurrent herpes simplex encephalitis.

This illustrates that an innate signaling lesion need not produce the same infections as a phagocyte defect.

The pathogen and affected organ may help localize the molecular pathway.

The association does not imply that every case of herpes encephalitis is hereditary.

Slide 36 · MyD88 transmits signals from multiple TLRs

Diverse TLR stimuli

MyD88 adaptor

Innate immune signaling

Antibacterial protection

Causal sequence — schematic

Slide 37 · MyD88 deficiency predisposes to destructive bacterial infection

MyD88 is downstream of several Toll-like receptors.

Defects affect signaling triggered by multiple microbial stimuli.

Severe destructive bacterial infections, especially pneumonia.

The phenotype differs from TLR3-associated herpes encephalitis.

Slide 38 · Cytokine deficiency can be inherited or acquired

Inherited defect

Mutation in a cytokine gene

Mutation in a cytokine receptor

Interruption of protective signaling

Acquired defect

Autoantibody directed at a cytokine

Neutralization of cytokine activity

Functional loss despite intact coding genes

Slide 39 · Type I interferons are major antiviral cytokines

Virus recognition

Type I IFN response

Antiviral host defense

Restriction of infection

Causal sequence — schematic

Slide 40 · Defective type I IFN immunity and severe viral disease

Inherited defects in type I IFN pathways can increase viral susceptibility.

Autoantibodies to type I interferons can create acquired cytokine dysfunction.

Severe forms of COVID-19 among associated viral presentations.

A pathway deficiency is a risk mechanism, not a deterministic clinical outcome.

Slide 41 · IL-12 and IFN-γ form a macrophage-defense axis

IL-12 signal

Th1 response

IFN-γ signal

Intracellular bacterial control

Causal sequence — schematic

Slide 42 · Mendelian susceptibility to mycobacterial disease

Mutations affecting IL-12 or IFN-γ receptor signaling impair protective responses.

Environmental mycobacteria of low usual virulence may cause disease.

This phenotype is termed Mendelian susceptibility to mycobacterial disease.

IL-12 / IFN-γ receptor defect

Reduced cellular defense

Environmental mycobacterial infection

Schematic

Slide 43 · Innate signaling defects: Use the organism pattern

Pathway impaired

Robbins-associated clinical pattern

TLR3 signaling

Recurrent herpes simplex encephalitis

MyD88 signaling

Severe pyogenic bacterial infections; pneumonia

Type I interferon immunity

Viral disease; severe COVID-19 forms

IL-12 / IFN-γ axis

Infection by environmental mycobacteria

Slide 44 · Complement has three initiation routes

Classical pathway

Antigen–antibody complexes activate C1

Involves early components including C2 and C4

Alternative pathway

Amplification on microbial surfaces

Can operate without antibody

Lectin pathway

Mannose-binding lectin recognizes carbohydrates

Converges on subsequent complement steps

Slide 45 · The C3 cleavage step is the shared hub

Classical / alternative / lectin

C3 convertase

C3a + C3b

C5 convertase

C5b–9 membrane attack

Functional sequence — schematic

Slide 46 · Complement protects in three distinct ways

Inflammation

C3a / C5a

Vascular reactions and leukocyte recruitment

Opsonization

C3b / iC3b

Enhanced phagocyte ingestion

Direct lysis

C5b–C9

Membrane attack complex

Slide 47 · C2 and C4 deficiencies affect classical activation

C2 deficiency is described as the most common complement protein deficiency.

C2 or C4 deficiency can reduce classical pathway activity.

Some affected individuals have bacterial or viral infections; Others remain asymptomatic.

Early classical pathway defect

Alternative pathway may persist

Variable clinical expression

Schematic

Slide 48 · Early classical deficiency can present as autoimmunity

C1q / C2 / C4 deficiency

Less efficient immune-complex clearance

Immune-complex persistence

SLE-associated phenotype

Causal sequence — schematic

Slide 49 · Why an immune deficiency may resemble SLE

Complement participates in removal of immune complexes.

Early classical components contribute to this clearance.

SLE may dominate in some patients deficient in C1q, C2, or C4.

The clinical phenotype therefore need not be recurrent infection alone.

Slide 50 · Properdin and factor D: Alternative-pathway defects

Properdin and factor D support alternative-pathway complement activity.

Inherited deficiency of either is uncommon.

These defects with recurrent pyogenic infections.

Alternative pathway impairment

Reduced complement protection

Recurrent pyogenic infection

Schematic

Slide 51 · C3 deficiency removes multiple complement defenses

C3 deficiency

Reduced complement effector activity

Impaired host defense

Severe recurrent pyogenic infection

Causal sequence — schematic

Slide 52 · C3 deficiency and immune-complex glomerulonephritis

Increased immune-complex–mediated glomerulonephritis in C3 deficiency.

C3 contributes to clearance of immune complexes as well as microbial defense.

Even when complement is deficient, inflammation may still be driven through Fc receptors.

A renal inflammatory complication can coexist with recurrent infection.

Slide 53 · Terminal complement deficiency targets membrane attack

Defect in C5, C6, C7, C8, or C9

Failed C5b–9 assembly

Reduced complement-mediated lysis

Recurrent Neisseria infection

Causal sequence — schematic

Slide 54 · Why Neisseria is a clue to terminal deficiency

The membrane attack complex perforates susceptible microbial membranes.

Neisseria because its thin cell wall permits complement-mediated lysis.

Meningococcal or gonococcal infections may recur when terminal lysis is deficient.

This pattern helps distinguish terminal defects from global C3 deficiency.

Slide 55 · Mannose-binding lectin deficiency

Mannose-binding lectin initiates the lectin pathway.

Inherited dysfunctional forms are associated with susceptibility to infections.

This defect interrupts recognition-dependent complement activation.

Defective mannose-binding lectin

Impaired lectin initiation

Reduced antimicrobial protection

Schematic

Slide 56 · Complement regulators protect host tissues

C1 inhibitor

Restrains protease systems including C1 and kallikrein

Prevents uncontrolled vasoactive mediator generation

CD55 / CD59

Cell-surface, GPI-anchored complement regulators

Help prevent complement injury to host cells

Factor H

Controls alternative-pathway amplification

Protects vascular and other host surfaces

Slide 57 · Hereditary angioedema: C1 inhibitor deficiency

Autosomal dominant C1-INH defect

Poor kallikrein restraint

Excess vasoactive mediator activity

Episodic tissue edema

Causal sequence — schematic

Slide 58 · Angioedema can threaten airway and gut

Edema may involve skin, larynx, or gastrointestinal mucosa.

Laryngeal swelling can cause life-threatening airway obstruction.

Gastrointestinal attacks can produce nausea, vomiting, and diarrhea.

Minor trauma or emotional stress may precede attacks; C1-INH concentrate for acute treatment.

Slide 59 · PNH is an acquired regulatory defect

Somatic PIGA mutation

Defective GPI anchoring

Loss of CD55 / CD59 protection

Complement-mediated red-cell lysis

Causal sequence — schematic

Slide 60 · Complement regulation in PNH: The cell-surface view

Without GPI-linked protective proteins, erythrocytes become vulnerable to terminal complement injury.

Protected host red cell: CD55 and CD59

PNH red cell: Deficient regulators

CD55 / CD59 present

Complement vulnerability

Slide 61 · Factor H connects regulation to vascular injury

Factor H constrains the alternative pathway through C3b regulation.

Defects in alternative-pathway regulators are associated with atypical hemolytic uremic syndrome.

Factor H gene variants have also been associated with age-related macular degeneration.

Regulatory failure

Excess host-surface complement activity

Tissue injury

Schematic

Slide 62 · Complement defects: Phenotype-oriented comparison

Defect group

Dominant association in Robbins

C1q / C2 / C4

Variable infection; SLE in some

Properdin / factor D

Recurrent pyogenic infection

C3

Severe pyogenic infection; immune-complex GN

C5–C9

Recurrent Neisseria infection

C1 inhibitor

Episodic skin / airway / GI edema

GPI-linked regulators

PNH / red-cell complement lysis

Slide 63 · A localization framework for innate immune defects

Presenting pattern

Potential checkpoint

Severe bacterial infection with poor tissue recruitment

Endothelial adhesion: LAD-1 / LAD-2

Giant granules with pigment / neurologic clues

Lysosomal trafficking: Chédiak–Higashi

Infection plus macrophage-rich granulomas

Oxidative killing: CGD

Recurrent HSV encephalitis or pyogenic pneumonia

TLR3 / MyD88 pathways

Environmental mycobacteria

IL-12 / IFN-γ signaling

Recurrent Neisseria

Terminal complement lysis

Slide 64 · Application: Recurrent invasive Neisseria infection

ILLUSTRATIVE TEACHING VIGNETTE

Teaching vignette: Repeated meningococcal or gonococcal infections occur in a patient without evidence in this vignette of a generalized leukocyte adhesion defect.

Question: Which complement function is particularly implicated?

Mechanistic answer: C5b–C9 membrane attack complex formation; Examine terminal pathway components.

Slide 65 · Integrative synthesis: The failed-defense checkpoint

Access infection site

Ingest and process microbes

Kill or signal

Opsonize / lyse microbes

Restrain self-injury

Functional sequence — schematic

Slide 66 · Textbook reference and scope

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

Primary section: Defects in Innate Immunity, within Immunodeficiency Diseases.

Mechanism context drawn from the supplied sections on normal innate immunity, inflammation, and complement; PNH details from the supplied hematology chapter.

Teaching diagrams in this lecture are original editable schematics, not pathology specimens.