Viral Immunopathology — Questions

Measles vaccines (measles-rubella [MR], measles-mumps-rubella [MMR], and measles-mumps-rubella-varicella [MMRV]) contain live attenuated virus that must replicate in the recipient to provoke immunity. About 5 to 15% of vaccinees develop a mild, transient maculopapular rash 5 to 12 days after vaccination, often with low-grade fever. This is the expected immune response to vaccine-strain replication: the same immunopathology as wild-type measles, markedly attenuated.

The reaction is not a hypersensitivity to excipients, not contamination, and not reactivation of a latent virus, and it is not driven by maternal antibody. Where serology is positive and the clinical picture is ambiguous, a vaccine-associated reaction is distinguished from breakthrough wild-type infection by genotyping (the vaccine strain is genotype A) at a reference laboratory, and by a low immunoglobulin M (IgM) to immunoglobulin G (IgG) ratio compared with primary wild-type infection.

Mechanism. The dominant mechanism is immune-complex disease driven by chronic B cell stimulation. Chronic exposure of B lymphocytes to hepatitis C virus (HCV) antigens (E2 binding CD81; antigen drive in intrahepatic lymphoid follicles) produces polyclonal, then oligoclonal, then monoclonal expansion. The expanded B cells secrete rheumatoid-factor-like immunoglobulin M (IgM) that binds polyclonal immunoglobulin G (IgG), forming type II mixed cryoglobulins. These and conventional immune complexes deposit in small- and medium-vessel walls, glomeruli and the dermoepidermal junction, activating complement and recruiting neutrophils.

Four examples (any four):

1. Mixed cryoglobulinaemic vasculitis: palpable purpura (leukocytoclastic vasculitis), arthralgia, peripheral neuropathy, glomerulonephritis.
2. Membranoproliferative glomerulonephritis: renal immune-complex deposition with proteinuria, haematuria, hypertension and progressive impairment.
3. B cell non-Hodgkin lymphoma (typically marginal zone): late clonal expansion; ~5 to 10% of those with mixed cryoglobulinaemia progress to overt lymphoma.
4. Porphyria cutanea tarda: photosensitive bullous skin disease on sun-exposed surfaces, via reduced hepatic uroporphyrinogen decarboxylase activity.

Other recognised manifestations include lichen planus, a Sjögren-like sicca syndrome, autoimmune thyroiditis and type 2 diabetes. Direct-acting antiviral (DAA) cure regresses most extrahepatic manifestations, an argument for treatment regardless of fibrosis stage.

A cytokine storm is a massive, self-amplifying and dysregulated release of pro-inflammatory cytokines, principally interleukin-6 (IL-6), interleukin-1, tumour necrosis factor, and interferon-induced chemokines, that is neither scaled to the infection nor switched off as it resolves. The result is widespread tissue injury rather than controlled defence: diffuse alveolar damage and the acute respiratory distress syndrome (ARDS), capillary leak, hypotension and multi-organ failure.

In severe COVID-19 it marks the hyperinflammatory phase, with raised IL-6 and ferritin and a tendency to microvascular thrombosis, and the same mechanism drives the lethal pneumonias of highly pathogenic avian influenza and is thought to have contributed to the exceptional mortality of the 1918 influenza pandemic. Because the damage is immune-mediated, treatment targets the response, with corticosteroids and IL-6 blockade in the most inflamed patients.

Virus-associated haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome in which the immune response, rather than the virus itself, drives the disease.

It is the extreme of the hyperinflammatory axis: a relentless, self-sustaining activation of CD8 cytotoxic T cells and macrophages. Normally the cytotoxic response kills infected cells and then terminates itself through perforin-dependent killing; when that off-switch fails, through an inherited defect of the perforin pathway (familial HLH) or an acquired one, the response cannot be shut down.

The activated lymphocytes and macrophages pour out cytokines (interferon gamma, interleukin-6, tumour necrosis factor and others) in a self-amplifying loop. Activated macrophages then engulf the host’s own blood cells (haemophagocytosis) in the bone marrow, spleen and liver, producing the progressive cytopenias.

Epstein-Barr virus (EBV) is the commonest viral trigger, infecting T or natural killer (NK) cells and driving continuous cytokine production, often in a host with an underlying defect of perforin-dependent killing. Cytomegalovirus is another, particularly in the immunocompromised.

Because the immune response is the disease, immunosuppression is therapeutic (immunomodulation, and etoposide-based protocols when severe) while the triggering infection is treated, a reversal of the usual principle that immunosuppression worsens infection.

Chronic hepatitis C virus (HCV) drives a spectrum of B cell disorders from benign polyclonal expansion through mixed cryoglobulinaemia to overt B cell non-Hodgkin lymphoma (NHL).

Pathogenesis. The dominant mechanism is chronic B cell stimulation by HCV antigens: E2 binds CD81 on B lymphocytes, driving polyclonal then oligoclonal then monoclonal expansion. A subset acquires further genetic lesions (most often t(14;18) BCL2 rearrangement) and progresses to lymphoma.

Spectrum. Polyclonal expansion, then type II mixed cryoglobulinaemia, then marginal zone lymphoma (splenic, nodal, or extranodal; the commonest HCV-associated NHL), and less often lymphoplasmacytic lymphoma or diffuse large B cell lymphoma (usually transformation of indolent disease). Around ~5 to 10% of those with mixed cryoglobulinaemia progress to overt lymphoma.

Clinical features. B symptoms, lymphadenopathy, splenomegaly, cytopaenias, extranodal disease (parotid, stomach, skin).

Diagnosis. Tissue biopsy with histology, flow cytometry and cytogenetics. Screen all newly diagnosed B cell NHL for HCV, and HCV-associated cases for human immunodeficiency virus (HIV) and hepatitis B virus (HBV) before any rituximab (the highest-risk drug for HBV reactivation).

Treatment. Direct-acting antiviral (DAA) therapy regresses indolent HCV-associated lymphomas (notably splenic marginal zone lymphoma), with a haematological response in around half. Combined DAA plus rituximab is standard for aggressive disease, with mandatory tenofovir or entecavir prophylaxis in any HBsAg- or anti-HBc-positive patient.

HAM/TSP (human T-lymphotropic virus type 1 [HTLV-1]-associated myelopathy / tropical spastic paraparesis) is a slowly progressive inflammatory myelopathy. It presents as a spastic paraparesis with brisk reflexes, bladder dysfunction and back pain, driven by immune-mediated infiltration of the thoracic spinal cord.

It is not a flaccid or acute process, not a peripheral neuropathy, not an optic neuritis, and not a cerebellar syndrome.

Hepatitis A virus (HAV) is not directly cytopathic. Very high viral loads accumulate in the liver well before any biochemical or histological evidence of injury, and the ALT rise coincides with the appearance of anti-HAV immunoglobulin M (IgM) and the cellular immune response.

The injury is immune-mediated, predominantly by CD8 cytotoxic T cells and multifunctional CD4 T cells acting on infected hepatocytes. This also explains why hepatitis A is self-limiting: once the adaptive response clears infected hepatocytes, no reservoir remains.

Measles produces a spectrum of central nervous system (CNS) complications defined by when they appear after the acute illness, the host’s immune status, and whether active or defective measles virus (MeV) is present in the brain.

Feature	ADEM	MIBE	SSPE
Full name	Acute disseminated encephalomyelitis (post-infectious)	Measles inclusion-body encephalitis	Subacute sclerosing panencephalitis
Timing after measles	Days to weeks (within the first week of rash)	Weeks to months	6 to 10 years (range 1 to over 30)
Host	Immunocompetent (usually over 2 years)	Immunocompromised	Immunocompetent (especially if infected under 2 years)
Mechanism	Post-infectious autoimmune: molecular mimicry, perivascular lymphocytic cuffing, demyelination	Active CNS infection by replicating MeV	Persistent CNS infection by defective MeV (mutated M, H, F genes; no virion assembly)
MeV in brain?	No, virus not detected	Yes, with virion production	Yes, but defective; no infectious virus recoverable
Incidence	~1 in 1,000 measles cases	Rare	~1 in 10,000 to 100,000
Clinical course	Monophasic, over weeks	Progressive over months	Progressive over years, with periodic remissions
Outcome	~10 to 20% mortality, frequent sequelae	Almost always fatal	Invariably fatal (1 to 3 years from onset)
Pathology	Demyelination, perivascular inflammation	Inclusion bodies in neurons and glia	Diffuse encephalitis, nuclear and cytoplasmic inclusions, patchy demyelination
MeV antibody in cerebrospinal fluid (CSF)?	No intrathecal synthesis	Variable, often poor	Markedly elevated, with oligoclonal immunoglobulin G (IgG) bands
Diagnosis	Clinical, magnetic resonance imaging (MRI) demyelination, CSF lymphocytic pleocytosis	CSF reverse-transcription PCR (RT-PCR) for MeV; biopsy if available	Diagnostic triad: clinical decline, periodic high-amplitude slow-wave electroencephalogram (EEG) complexes, intrathecal MeV antibody

Key discriminators. Time after rash separates them first: ADEM in days to weeks, MIBE in months, SSPE in years. Host status separates them next: MIBE is the encephalitis of the immunocompromised, whereas SSPE strikes the previously immunocompetent young child. Presence of virus in the brain distinguishes the three pathologies: absent in ADEM (autoimmune), actively replicating in MIBE, and defective in SSPE. All three are largely preventable by measles vaccination.