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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5210_Библиотеки_им_академика_М_И_Перельмана
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Figure11.1 Lesions of systemic lupus erythematosus presenting on the right buccal mucosa and palate as
erosions that resemble erosive lichen planus.
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Figure11.2 Lesions of systemic lupus erythematosus presenting on the left buccal mucosa and palate as
erosions that resemble erosive lichen planus.
Figure11.3 Lesions of systemic lupus erythematosus presenting on the palate as erosions that resemble
erosive lichen planus.
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Figure11.4 Lesions of systemic lupus erythematosus presenting on the right ventrolateral tongue as
erosions that resemble erosive lichen planus. At this location, this clinical presentation would also include
a differential diagnosis of erythroplakia and squamous cell carcinoma.
heart valve abnormalities and Libman- Sacks endocarditis, which is a nonbacterial thrombotic
endocarditis. Peripheral neuropathy, seizures, cognitive impairment, anxiety and depression have
all been recorded in patients with SLE. The symptoms of lupus wax and wane and mimic those of
several other conditions. Therefore, diagnosis of the condition requires a thorough medical history,
physical exam and laboratory tests for antinuclear antibodies (ANA), antiphospholipid antibodies,
ant- smith and anti- double- strand DNA antibodies. A comprehensive metabolic panel and urine
samples for renal function may also be needed. Skin or mucosal biopsy may be performed to show
characteristics but not pathognomonic histopathological features and a positive lupus band test.
Management of the condition involves a team consisting of a family physician, cardiologist, dermatologist, endocrinologist, pulmonologist, nephrologist, rheumatologist and a mental health professional. Drug therapy is individualised depending on the symptoms and organs involved. Mild
disease may be treated with hydroxychloroquine NSAIDs with or without corticosteroids like prednisone. A steroid- sparing drug like azathioprine, belimumab or anifrolumab may be added to control symptoms associated with moderate disease. Severe disease requires inpatient care with added
therapy, including rituximab, cyclophosphamide and mycophenolate. Newer drugs such as antibodies to IFN- I receptor (Anifrolumab), anti- interleukin six receptor drugs, and more unique anti CD20monoclonal antibodies like Obinutuzumab are undergoing clinical trials(4, 5).
11.2.4 Type IV Hypersensitivity Disorders (Delayed/Cell- mediated)
Type IV hypersensitivity reactions evolve over 12 hours (delayed), including previously sensitised
T- cell (cell- mediated) release of lymphokines and recruitment of other cell types like macrophages
and effector cytotoxic T- cells. Three kinds of type IV hypersensitivity disorders are recognised.
They are contact hypersensitivity reactions, tuberculin- type hypersensitivity reactions and granulomatous hypersensitivity reactions.
11.2.4.1 Contact Hypersensitivity Reactions
Contact hypersensitivity reactions or contact dermatitis occur at the point of contact with an allergen. Commonly implicated allergens include poison ivy (pentadecylcatechol), nickel, acrylics,
latex, preservatives, industrial chemicals and chromate. They penetrate the skin, sensitise the
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antigen- presenting Langerhans cells, and stimulate keratinocyte release of pro- inflammatory
cytokines. Sensitisation of Langerhans cells results in the formation of CD4+ memory T- cells in
the regional lymph nodes. This process of sensitisation takes from 10 to 14days. Reintroduction of
the allergen results in its presentation to the CD4+ memory T- cells with activation of inflammation, all within 48– 72 hours. The area of the skin exposed to the allergen shows an erythematous
pruritic rash accompanied by oedema and vesiculation.
11.2.4.2 Oral Contact Hypersensitivity Reactions
Oral mucosal contact hypersensitivity reactions have also been described against dental restorative
materials having zinc, indium, palladium and chromium as in dental amalgam. The reaction has a
lichenoid appearance clinically (Figure11.5) and histopathologically but is limited to the mucosal
surface adjoining the restoration. Histopathologically, basal cell degeneration and a dense band of
chronic inflammation of the lamina propria are seen (Figure11.6). These lesions also show deeper
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Figure11.5 A lesion of contact lichenoid metal reaction with ulceration over the left buccal mucosa.
Figure11.6 Histopathology of a lichenoid contact metal reaction shows basal cell degeneration and a
dense band of chronic inflammation of the lamina propria.
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Figure11.7 Histopathology of a lichenoid contact metal reaction also shows deeper lymphocytic
infiltrates, germinal centers, and perivascular infiltrates of lymphocytes.
lymphocytic infiltrates, germinal centres and perivascular infiltrates not seen in lichen planus
(Figure11.7). Patients may be asymptomatic or present with burning soreness. Symptoms are
amplified due to poor oral hygiene and candidal infection. Replacement with plastic restorations
results in the resolution of the lesions.
11.2.4.3 Tuberculin- type Hypersensitivity
Tuberculin- type hypersensitivity reaction is seen after an intradermal injection of a purified protein derivative of the tubercle bacillus. Previously exposed (sensitised) individuals develop a firm
to hard area of erythematous skin swelling within 48– 72 hours of the injection. Soluble antigens
from other organisms, such as Mycobacterium leprae, Bartonella henselae and Leishmania tropica, also produce a similar reaction in sensitised individuals. The mechanism involves the activation of memory T- cells that release cytokines and vascular adhesion molecules to recruit
leucocytes, monocytes and CD4+ T- cells. This hypersensitivity reaction resolves within a week.
Antigen persistence may result in a tuberculin- type hypersensitivity transforming into a granulomatous hypersensitivity.
11.2.4.4 Granulomatous Hypersensitivity Reactions
11.2.4.4.1
Oro- facial Granulomatosis (OFG)
Granulomatous hypersensitivity reactions result from persistence of an antigen within a
macrophage or the tissue. Its histopathological morphology defines it as granulomas consisting of
lymphocytes, epithelioid macrophages and multinucleated giant cells. Acentral zone of necrosis
may or may not be seen. The antigen is known in diseases such astuberculosis and leprosy and is
unknown in sarcoidosis, Crohn’s disease and OFG (Figures 11.8– 11.11). Non- immunological
stimuli may also produce granulomatous hypersensitivity reactions. Examples include foreign
particulate material that resists digestion, such as talc, non- resorbable suture material, silica and
similar particulate substances (Figures 11.12 and11.13). Granulomatous reactions are clinically
significant in diseases such as tuberculosis, leprosy, sarcoidosis, Crohn’s disease and OFG.
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Figure11.8 A linear fissure of the oral mucosa in a patient with Crohn’s disease.
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Figure11.9 Histopathology of the linear fissure of Crohn’s disease demonstrating granulomatous
inflammation.
Figure11.10 Histopathology of the linear fissure of Crohn’s disease demonstrating granulomatous
inflammation with granulomas consisting of multinucleated giant cells, macrophages, and lymphocytes.
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Figure11.11 Histopathology of the terminal ileum in Crohn’s disease demonstrating transmural
granulomatous inflammation with granulomas consisting of multinucleated giant cells, macrophages, and
lymphocytes.
Figure11.12 Right buccal mucosa with inflammation and abscess associated with embedded
suturematerial.
Figure11.13 Histopathology of the embedded suture material with surrounding granulomatous
inflammation.
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11.3 Immunodeficiency Disorders
11.3 Immunodeficiency Disorders
Immunodeficiency disorders result from a defect or a combination of defects associated with the
immune system. The defect may be specific to the humoral or cell- mediated immune response or
be non- specific and related to the function of the complement system, macrophages or innate
immunity of leucocytes. Further, immunodeficiency may arise because of secondary factors such
as drugs, chronic diseases, malignancies, radiation, nutritional deficiencies and infections such as
Acquired Immunodeficiency Syndrome (AIDS). An immunodeficiency state renders the individual prone to infections and certain cancers.
11.3.1 Primary Immunodeficiencies (Intrinsic)
These are immunodeficiencies intrinsic to the non- specific or the specific arm of the immune system and not in response to extrinsic (secondary) factors.
11.3.1.1 Non- specific Deficiencies
Many inherited defects of the complement system have been described. A deficiency of complement proteins of the classical pathway, including C1q, C1r, C1s, C2, C3 and C4, results in an
immune- complex autoimmune- like condition resembling SLE. C2 and C3 deficiency results in
bacterial infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis, Pseudomonas aeruginosa, Staphylococcus aureus and Mycoplasma pneumoniae, while a
C5– C9 deficiency and a deficiency of factor D or properdin of the alternate pathway causes invasive
infections by Neisseria meningitidis. Regulatory components factor H and factor I deficiencies result
in recurrent haemolytic- uraemic syndrome and membranoproliferative glomerulonephritis.
A deficiency of C1 esterase inhibitor, which is a regulatory component of the classical activation
pathway, causes angioedema that results in recurrent and sometimes fatal oedema of the gut, face,
oral cavity and upper respiratory tract due to lack of regulation of the kallikrein- kinin system with
the uncontrolled release of bradykinin. Deficiency is inherited as an autosomal dominant trait.
Phagocyte defects may be related to either their numbers or their function. Examples of the
former include severe congenital neutropenia (SCN) due to a mutation in the neutrophil elastase
ELA2 gene, which may also result in cyclic neutropenia with 21- day cycles of fall in neutrophil
counts. These mutations risk myelodysplasia and myeloid leukaemia in affected patients. Other
examples of neutropenia include SCN associated with mutations of the Wiskott– Aldrich syndrome (WAS) protein gene WASP and SCN associated with Barth syndrome. Examples of phago-
cyte defects related to their function include defects of Toll- like receptors (TLRs), defective
production of reactive oxygen species, leucocyte adhesion deficiency (LAD) 1, 2 and 3, defects of
interleukin interferon signalling pathway, and defective vesicle and lysosomal fusion. TLRs are
membrane molecules that recognise bacterial glycolipids, nucleic acids and lipopolysaccharides.
IRAK4 and MYD88 gene mutations result in TLR defects causing severe invasive pyogenic infections, while mutations in UNC93B result in herpes simplex encephalitis. Defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex due to mutations in several
genes that encode components such as gp91
of phagocytes to use oxidative bursts to digest pathogens. This results in the persistence of infections, as in chronic granulomatous diseases. Examples include recurrent severe cutaneous and
hepatic infections caused by S. aureus, Serratia marcescens Nocardia and Mycobacteria species,
and fungal infections by Candida and Aspergillus species. Three types of LAD are recognised.
phox
, p22
phox
, p47
phox
and p67
phox
result in the inability
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LAD1 results from ITGB2 gene mutation with unstable adhesion of leucocytes to the endothelial
cells. LAD2 results from mutation of the GDP- fucose transporter with reduced expression of
Sialyl- Lewis- X ligand for E- selectin with resultant impaired rolling of leucocytes over the
endothelial cells. LAD3 is a result of the mutation of kindlin- 3 with poor integrin signalling.
These deficiencies cause severe infections without pus formation, poor wound healing, severe
periodontitis and early tooth loss. Macrophage IL- 12 binds to T and NK cells, resulting in the
release of IFN- γ. This causes the lysis of a pathogen. Inherited defects of the IL- 12/IFN- γ system
are known to cause mycobacterial infections such as those by Mycobacterium avium,
Mycobacterium Kansassi, and Listeria, Histoplasma, Salmonella and viruses, especially by
Epstein– Barr virus (EBV). Chediak- Higashi syndrome is autosomal recessive impaired cellmediated cytotoxicity due to mutations in a gene encoding lysosomal trafficking regulator (LYST)
involved in the fusion of intracytoplasmic vesicles and lysosomes. This affects neutrophils,
macrophages, dendritic cells, NK cells and cytotoxic T- lymphocytes with resultant infections by
pyogenic bacteria(6).
11.3.1.2 Specific Deficiencies
Specific immunodeficiencies involve abnormalities of the T- lymphocytes and the B- lymphocytes.
Defects in B- lymphocytes and their immunoglobulins result in pyogenic infections by encapsulated bacteria. Defects in T- lymphocytes result in opportunistic fungal and viral infections.
B- lymphocyte deficiencies, including antibody deficiencies, cause severe respiratory infections
ranging from otitis media to sinusitis and pneumonia. Infections of the skin, urinary tract infections, meningitis and arthritis, viral infections and GI infections by Giardia also occur. Antibody
deficiencies depend on B- cell development, maturation and their function. B- lymphocyte deficiencies include X- linked agammaglobulinemia (XLA), IgA and IgG subclass deficiencies,
immunodeficiency with hyper- IgM phenotype (HIGM), hypogammaglobulinemia of infancy and
CVID. Defects in intracytoplasmic adaptor molecule B cell linker protein (BLNK) and Bruton
tyrosine kinase (BTK) cause XLA. BTK defects account for 85% of early- onset agammaglobulinemias, mutations in heavy μ chain gene immunoglobulin heavy constant mu (IGHM) account for
5%, while mutations in BLNK, λ5, Igα and Igβ account for the rest of the cases. In all these cases, a
block at the pro- B to the pre- B stage of B- cell differentiation in the bone marrow results in a marked
reduction in circulating B- lymphocytes. Enteroviral infections, meningoencephalitis, dermatomyositis and mycoplasma infections occur if patients are not treated with replacement immunoglobulin therapy. IgA deficiency is the most common primary immunodeficiency, with a prevalence of
1:700worldwide. The majority of patients are asymptomatic, and others suffer recurrent infections
and immune- complex (type III) hypersensitivity. Patients with infections tend to demonstrate
associated IgG2 deficiency. Mutations in AICDA and UNG genes cause intrinsic defects of classswitch recombination with low IgG, IgA and IgE levels, whereas IgM levels are increased to more
than 200 mg/dl. This results in immunodeficiency with HIGM. Patients suffer from repeated pyogenic infections. Hypogammaglobulinemia of infancy is transient, with low immunoglobulin levels for up to two years. Spontaneous normalisation occurs but is variable. Low levels are associated
with recurrent upper and lower respiratory tract infections. The persistence of infections beyond
two years of age is related to a low number of memory B cells. Common variable immuno deficiency disorders (CVIDs) affect adults mainly. They are a group of clinically heterogeneous conditions associated with low levels of one or more immunoglobulin isotypes and impaired antibody
production in response to infections and vaccines. Patients suffer from upper and lower respiratory
tract infections, including pneumonia. Inflammatory bowel disease, other granulomatous lesions
and lymphoma have also been recorded in these patients.
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11.3 Immunodeficiency Disorders
T- lymphocyte deficiencies result in opportunistic infections. T- cell deficiencies include failure of
class II MHC molecule expression on antigen- presenting cells, immunodeficiencies caused by
thymic defects, deficiencies associated with other diseases and severe combined immunodeficiency (SCID). Development of CD4 T- helper cells is dependent on MHC class II molecules in the
thymus. The defect is more common in some parts of the world, such as North Africa, and is characterised by CD4lymphopenia. The diagnosis requires the exclusion of other causes of CD4lymphopenia, such as Human Immunodeficiency Virus (HIV) and other T- cell lymphotropic virus
infections, and immunosuppressive therapy. The clinical spectrum of diseases includes those
caused by cryptococcus neoformans, candida species, Pneumocystis jiroveci and mycobacteria.
DiGeorge syndrome (DGS) arises from a defective thymus. It is part of a larger spectrum of deficiencies arising from impaired development of the third and fourth pharyngeal arches and
pouches. Other associated defects include impaired parathyroidism, heart abnormalities, facial
dysmorphisms, feeding difficulty and psychiatric disorders. Deletions of chromosome 22q11 and
10p 13– 14 have been observed. Facial features include hypertelorism, low- set ears, shortened
upper lip philtrum, cardiac and aortic defects and neonatal tetany due to parathyroid aplasia.
Immunologic deficiencies may be associated with diseases with multisystem manifestations, such
as WAS and hereditary ataxia- telangiectasia (AT). WAS is an X- linked condition characterised by
mutations in the WASP gene that encodes for haematopoetic cells specific actin cytoskeleton with
resultant defects in leucocytes, including T- cells, platelets and thrombocytopenia. Progressively
worsening T- cell function results in severe opportunistic infections. AT is an autosomal recessive condition. The clinical spectrum of disease includes a wobbly gait (ataxia), ocular telangiectasia, increased risk of infections (especially those of the lungs and sinuses) and tumours.
Immunodeficiency is associated with a progressive decrease in T- cell counts, T- cell function, and
IgA, IgG2 and IgG4 hypogammaglobulinemia. A defect in DNA repair mechanisms may cause an
increased incidence of tumours. Severe combined immunodeficiencies are a variable group of disorders with defective development and function of both T and B lymphocytes. Adenosine deaminase deficiency results in impaired survival of T- cell precursors and B- cells with extreme
lymphopenia and severe neutropenia. Purine nucleoside phosphorylase deficiency results in more
T- cell impairment than B- cell. Patients with SCIDs show infections of bacterial, viral and fungal
pathogens early in life. P. jiroveci pneumonia, cytomegalovirus (CMV), adenovirus, respiratory
syncytial visrus (RSV) and parainfluenza virus infections of the lungs are common(6).
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11.3.2 Secondary Immunodeficiencies
Secondary immunodeficiencies are much more common than primary immunodeficiencies.
Theimmune response may be impaired due to factors that are extrinsic to the immune system.
These factors alter skin and mucosal barriers, impair phagocytosis and cytotoxicity, result in
impaired production and function of immunoglobulins and impact T- helper cell function.
Neonates and prematurity are associated with immature innate and adaptive immune responses.
Immunosenescence and age- related changes include a decrease in TLR function, chemotaxis,
phagocytosis and cytokine production – thymic involution results in a decrease in T- cells.
Malnutrition has wide- ranging effects on the immune system and includes thymic atrophy,
reduced cellularity in the spleen, reduced levels of IL- 1, IL- 6, TNF- α and complement system com-
ponents. Neutrophil chemotaxis and NK cell cytotoxicity are also reduced, with reduced effector T
and circulating B cells. Hyperglycemia reduces neutrophil function and cytokine production.
Nephropathies of chronic renal disease associated with proteinuria induce hypogammaglobulinemia. Drugs, including anti- inflammatory and immunosuppressive agents, protein kinase
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inhibitors and biological agents, cause immunosuppression. Used in treating autoimmune disorders, malignancies, transplant rejection and graft- versus- host disease, they are directed to act upon
immune cells and cytokines. The most widely used among these drugs are corticosteroids that suppress proinflammatory cytokines and interleukins, tumour necrosis factor- α, interferon- gamma
and prostaglandins. They also cause neutropenia and lymphopenia. The result is that patients suffer from viral, bacterial and fungal infections and reduced wound healing. Other effects include
osteoporosis, diabetes mellitus, cataracts, hypertension, adrenal axis suppression and cushing
syndrome. Antiepileptic medications are also known to cause gammaglobulin deficiency.
Immunosuppression may also follow extensive trauma, burns and major surgery, including splenectomy and thymectomy. Individuals affected by conditions such as trisomy 21 (down syndrome),
monosomy XO (Turner syndrome), haematological malignancies, myelofibrosis, aplastic anaemia
and cystic fibrosis may also develop immunosuppression. Infections such as HIV, measles, mycobacterial infections and coronavirus disease also cause immunosuppression. Other extrinsic factors
of immune deficiency include UV radiation exposure, high altitude and space travel(7, 8).
11.3.2.1 HIV Infection and AIDS
AIDS was first defined in the 1980s. It is caused by infection with the HIV. Approximately 38million people are known to be living with this infection, with one million deaths annually. 70% of
patients are in Africa. Without antiretroviral chemotherapy, HIV infection progresses to AIDS,
which is characterised by malignancies and opportunistic infections causing death. The disease is
transmitted sexually, vertically, from infected mothers to their infants and by exchange of contaminated blood among intravenous drug users.
11.3.2.1.1 Virology andImmunopathogenesis
The HIV is a double- stranded RNA retrovirus. It infects mainly CD4+ helper T- cells. Its genome
contains three structural genes: gag, pol and env. Pol protein produces three enzymes: integrase,
reverse transcriptase and protease. Protease cleaves the viral proteins, and reverse transcriptase
converts the viral RNA into DNA. The integrase permits the incorporation of viral DNA into
the CD4+ cell genome and then uses the host cells’ replicative mechanisms to produce more
viruses. Entry into the CD4+ cell is facilitated by viral envelope proteins gp120 and gp41. T- cell
lymphopenia results from HIV- induced apoptosis, viral cytopathic effect and cytotoxicity to virally
infected cells.
11.3.2.1.2 Clinical Syndrome
Several weeks after infection, patients develop flu- like symptoms, including a fever, myalgia, fatigue
and headaches. These symptoms correlate with the initial viremia. They subside spontaneously, and
the acute phase now transitions into a latency period. The latency period can last 10 years, during
which there is a progressive loss of CD4+ cells. There is a lack of signs and symptoms during latency
3
until the CD4+ counts reach below 200 cells/mm
. At this time, viral loads are high, and the patient is
now profoundly immunosuppressed, resulting in AIDS. Immunosuppression causes a variety of
opportunistic infections and malignancies. The clinical syndrome now includes fever, weight loss,
diarrhoea, generalised lymphadenopathy, superficial and deep mycotic infections, protracted viral
infections and malignant neoplasms such as Kaposi sarcoma and AIDS- associated EBV lymphoma.
Oral lesions of AIDS include human papilloma virus (HPV) venereal warts known as condyloma
acuminatum, herpes simplex virus ulcers, aphthous- like ulcers, candidiasis, histoplasmosis, linear
gingival erythema, EBV hairy leucoplakia, necrotising periodontitis and stomatitis, Kaposi sarcoma and
EBV lymphoma. Infection- related multi- organ disease results in death in the absence of treatment.
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