IMMUNOLOGY

BY- SHADMA KHAN

ROLL NO. – BT2008
M.Sc. SEM II
SUBMITTED TO- VIDYAMEENAKSHI MA’AM
 IMMUNODEFICIENCY

Immunodeficiency, also known as immunocompromisation, is a

state in which the immune system's ability to fight infectious diseases and cancer is
compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic
factors that affect the patient's immune system. Examples of these extrinsic factors
include HIV infection and environmental factors, such
as nutrition.[1] Immunocompromisation may also be due to genetic diseases/flaws. An
example here is SCID.

In clinical settings, immunosuppression by some drugs, such as steroids, can either be

an adverse effect or the intended purpose of the treatment. Examples of such use is in organ
transplant surgery as an anti-rejection measure and in patients suffering from an overactive
immune system, as in autoimmune diseases. Some people are born with intrinsic defects in
their immune system, or primary immunodeficiency.[2]

A person who has an immunodeficiency of any kind is said to be immunocompromised. An

immunocompromised individual may particularly be vulnerable to opportunistic infections,
in addition to normal infections that could affect anyone.[3] It also decreases cancer
immunosurveillance, in which the immune system scans the body's cells and
kills neoplastic ones.

COMMON VARIABLE IMMUNODEFICIENCY: A NEW AT AN OLD DISEASE

Types

By affected component

 Humoral immune deficiency (including B cell deficiency or dysfunction), with signs or

symptoms depending on the cause, but generally include signs
of hypogammaglobulinemia (decrease of one or more types of antibodies) with
presentations including repeated mild respiratory infections,
and/or agammaglobulinemia (lack of all or most antibody production) which results in
frequent severe infections and is often fatal.[4]
 T cell deficiency, often causes secondary disorders such as acquired immune deficiency
syndrome (AIDS).[5]
 Granulocyte deficiency, including decreased numbers of granulocytes (called
as granulocytopenia or, if absent, agranulocytosis) such as of neutrophil
granulocytes (termed neutropenia). Granulocyte deficiencies also include decreased
function of individual granulocytes, such as in chronic granulomatous disease.
 Asplenia, where there is no function of the spleen
 Complement deficiency is where the function of the complement system is deficient

In reality, immunodeficiency often affects multiple components, with notable examples

including severe combined immunodeficiency (which is primary) and acquired immune
deficiency syndrome (which is secondary).

Primary immunodeficiency

Primary immunodeficiency disorder (PID) refers to a heterogeneous group of disorders

characterized by poor or absent function in one or more components of the immune system.
Over 130 different disorders have been identified to date, with new disorders continually
being recognized [1,2]. Most PIDs result from inherited defects in immune system
development and/or function; however, acquired forms have also been described . It is
important to note that PIDs are distinct from secondary immunodeficiencies that may result
from other causes, such as viral or bacterial infections, malnutrition, or treatment with
drugs that induce immunosuppression.

With the exception of immunoglobulin A (IgA) deficiency, PIDs are rare; the estimated
prevalence of these disorders in the United States is approximately 1 in 1200 live births. IgA
deficiency is the most common PID, occurring in approximately 1 in 300 to 1 in 500 persons

The clinical presentation of PIDs is highly variable; however, most disorders involve
increased susceptibility to infection. In fact, many PIDs present as “routine” infections (often
of the sinuses, ears and lungs) and, therefore, may go undetected in the primary-care
setting. The accurate and timely diagnosis of these disorders requires a high index of
suspicion and specialized testing. Therefore, consultation with a clinical immunologist who
is experienced in the evaluation and management of immunodeficiencies is essential, since
early diagnosis and treatment are critical for preventing significant disease-associated
morbidity and improving patient outcomes [5-7]. This article provides an overview of the
major categories of PIDs as well as strategies for the timely identification, diagnosis and
management of these disorders.

Classification
 PIDs
are broadly classified according to the component of the immune system that is primarily
disrupted: adaptive or innate immunity (see An Introduction to Immunology and
Immunopathology in this supplement for more information on adaptive and innate
immunity). Table presents a select list of PIDs grouped according to this system

Classification of PIDs: examples and typical clinical presentations

 Classification and examples Clinical presentation

Disorders of adaptive immunity

T-cell (cellular) immunodeficiency

► IFN-γ/IL-12 Atypical mycobacterial and salmonella
► AIRE mutations infections
Mucocutaneous candidiasis (thrush) and
autoimmune endocrinopathy
 Classification and examples Clinical presentation

B-cell (antibody-mediated)
immunodeficiency Recurrent sinopulmonary infections with
► XLA encapsulated bacteria
► CVID Autoimmune disease and increased risk of
► Selective IgA deficiency malignancy in CVID
► Specific antibody deficiency
► IgG subclass deficiency

CID
► Wiskott-Aldrich syndrome Thrombocytopenia with bleeding and
bruising; eczema; recurrent bacterial and viral
infections; autoimmune disease

► Ataxia telangiectasia Chronic sinopulmonary disease; cerebellar

ataxia (difficulty with control of movement);
 Classification and examples Clinical presentation

small, dilated blood vessels of the eyes and

skin; malignancy

► DiGeorge syndrome Hypoparathyroidism; seizures; cardiac

abnormalities; abnormal facies; infection

► SCID Severe, recurrent opportunistic infections;

• T- , B+ failure to thrive; diarrhea; rash
– γc deficiency
– JAK3 deficiency
• T- , B -
– ADA deficiency
– RAG 1/2 deficiency
 Classification and examples Clinical presentation

Disorders of innate immunity

Phagocyte defects
► Chronic granulomatous disease Severe infection; abscesses with granuloma
► Hyper IgE syndrome formation
► Leukocyte adhesion deficiency Chronic dermatitis; recurrent, severe lung
infections; skin infections; bone fragility;
 Classification and examples Clinical presentation

failure to shed primary teeth

Recurrent, severe bacterial infections; poor
wound healing; delayed separation of the
umbilical cord

Complement defects
► Deficiency in early complement SLE–like syndrome, rheumatoid disease,
pathway components (C1q, C1r, C2, C4) multiple autoimmune diseases, infections

► Deficiency in late complement Neisserial infections, SLE-like syndrome

pathway components (C5, C6, C7, C8,
C9)

► C3 and regulatory components Recurrent infections with encapsulated

bacteria

AIRE, autoimmune regulator; CVID, common variable immunodeficiency; IgG,

immunoglobulin G; IgE, immunoglobulin E; IgA, immunoglobulin A; IFNγ, interferon-
gamma; IL, interleukin; CID, combined immunodeficiency; SCID, severe combined
immunodeficiency; XLA, X-linked agammaglobulinemia; SLE: systemic lupus
erythematosus; JAK3, Janus kinase 3; ADA, adenosine deaminase; RAG, recombination
activating gene

Disorders of adaptive immunity

T cells and B cells are the primary cells of the adaptive immune system. B cells mediate
antibody production and, therefore, play a major role in antibody-mediated (humoral)
immunity. T cells, on the other hand, govern cell-mediated immune responses. Defects
occurring at any stage of T-cell development, differentiation and maturation lead to T-cell
(cellular) immunodeficiency disorders, while defects relating to B-cell development and/or
maturation result in B-cell (antibody-deficiency) disorders. Since B-cell-mediated antibody
production requires intact T-cell function, most T-cell defects lead to combined (B- and T-
cell) immunodeficiency disorders (CIDs)

Disorders of innate immunity

Innate immune responses represent the first line of defense against potentially invading
organisms. Appropriate recognition of threats and induction of the inflammatory cascade
are essential steps in the removal of these organisms from the system. Failure of the innate
system to identify pathogens delays the induction of the immune response and may worsen
outcomes of infection.

Numerous cells and proteins are involved in the innate immune response including
phagocytes (neutrophils and macrophages), dendritic cells, and complement proteins.
Phagocytes are primarily responsible for phagocytosis, the process by which cells engulf and
eliminate invading pathogens. Complement proteins function to identify and opsonize
(coat) foreign antigens, rendering them susceptible to phagocytosis. Defects in the
development and function of any of these elements of innate immunity may lead to PIDs.

Secondary immunodeficiencies, including HIV

infection
Secondary immunodeficiencies are far more common than primary immunodeficiencies,
which are, by definition, caused by genetic defects affecting cells of the immune
system.1 Secondary immunodeficiencies result from a variety of factors that can affect a host
with an intrinsically normal immune system, including infectious agents, drugs, metabolic
diseases, and environmental conditions. These deficiencies of immunity are clinically
manifested by an increased frequency or unusual complications of common infections and
occasionally by the occurrence of opportunistic infections (Fig 1). The secondary
immunodeficiencies have a wide spectrum of presentation, depending on the magnitude of
the offending external condition and on the host susceptibility. For example, the
immunodeficiency induced by the use of corticosteroids and other immunosuppressive
drugs depends on the dose used2,3 and, to a lesser degree, on concomitant disease processes
of the host, such as the presence of sepsis. AIDS, resulting from infection by HIV, is the best
known secondary immunodeficiency largely because of its prevalence and its high mortality
rate if not treated. However, the most common immunodeficiency worldwide results from
severe malnutrition, affecting both innate and adaptive immunity.4 The restoration of
immunity in secondary immunodeficiencies is generally achieved with the management of
the primary condition or the removal of the offending agent. We summarize reports of
immune defects occurring in a variety of clinical scenarios (Table I), with special emphasis
on HIV infection. We selected diseases and conditions based on their frequent presentation
in general medical practice and their relevance for allergists and immunologists. We do not
discuss immunomodulating mAbs and fusion proteins, which are covered in Chapter 28 of
this primer.5
EXTREMES OF AGE: NEWBORN PERIOD AND
ADVANCED AGE
Newborn period
Neonates have an increased susceptibility to common and opportunistic infections and
sepsis compared with older children.6 There is an inverse association of infection
susceptibility and the age of prematurity. In early life there are fewer marginal-zone B cells
in lymphoid tissue and a decreased expression of CD21 on B cells, thus limiting the ability of
B cells to develop specific responses.7 Although they can develop humoral responses to some
antigens after exposure in utero, impaired immunity in newborns can be attributed to the
relative lack of maturity of secondary lymphoid organs, including the lymphoid tissue
associated to mucosa in the gastrointestinal and respiratory tracts. This immaturity is
related to the absence of memory cell development because of the relative isolation provided
by the maternal environment. In addition, premature infants are more vulnerable to
infections because of the absence of maternal IgG transfer before 32 weeks of gestational age.
Other significant recent observations described at this early age are related to innate
immunity mechanisms, such as a decreased neutrophil storage pool, as defined by the
ability of neutrophilia to develop in response to an infection; decreased in vitro neutrophil
functions (ie, phagocytosis, oxidative burst, chemotaxis, and adhesion); capacity to develop
a neutrophil extracellular trap8; decreased natural killer cell activity; decreased Toll-like
receptor signaling; decreased production of cytokines; and reduced complement
components.

Advanced age
Among the elderly, some subjects experience malignancies and an excessive number of
infections caused by viruses and bacteria, reflecting a decrease in the immune defenses,
particularly in the cellular compartment. Decreased delayed-type hypersensitivity skin
reactions and decreased lymphocyte proliferative responses to mitogens can be
demonstrated in this patient population. This relative impairment of the immune response
has been linked to the development of T-cell oligoclonality together with a limited capacity of
the thymus to generate naive T cells and therefore reduced responses to new antigens.
Oligoclonal expansion of CD8+ T cells begins in the seventh decade of life, which results in
the skewing of the T-cell repertoire and an increased number of differentiated memory
CD8+ T cells.9 Advanced age is similarly associated with a restricted B-cell diversity
repertoire and a limited response to vaccines; however, there is also an increased number of
total memory B cells and increased total IgG levels. The innate immunity might be
compromised in the elderly, with increased breakdown of skin and mucosal barriers and
slow healing processes caused by metabolic and endocrinologic changes associated with
aging. A diminished production of hematopoietic growth factors has been postulated to
occur in the elderly, resulting in decreased ability to upregulate the production and function
of macrophages and neutrophils.10 Some subjects are at higher risk of infections when these
immunologic defects are combined with other environmental factors, such as malnutrition
or the concomitant presence of chronic inflammation caused by autoimmunity or persistent
infections.11 Progress in understanding the aging-associated immune defect is of importance
to optimize protective immunity against preventable infectious diseases.12

Go to:

MALNUTRITION
Worldwide, protein-calorie malnutrition is the most common cause of
immunodeficiency.13 Malnutrition can result from limited access to food sources and chronic
diseases that induce cachexia, such as neoplastic diseases. Diarrhea caused by infections
and respiratory tract infections are common. T-cell production and function decrease in
proportion to the severity of hypoproteinemia; however, specific antibody titers and immune
responses to vaccines can be detected in a malnourished subject for a relatively prolonged
period. Eventually, these immune responses decrease if malnutrition persists. The deficiency
of micronutrients (eg, zinc and ascorbic acid) contributes to increased susceptibility to
infections through the weakening of barrier mucosa, therefore facilitating a pathogen’s
invasiveness.14,15 Other essential molecules have been shown to have specific roles in the
immune system; for example, vitamin D appears to be necessary in the macrophage activity
against intracellular pathogens, remarkably Mycobacterium tuberculosis (Fig
2).16 Correction of the nutritional deficiencies often results in the resolution of these
immunologic defects.
METABOLIC DISEASES: DIABETES
MELLITUS AND UREMIA
Many disease processes originating from dysfunctional metabolic pathways significantly
affect the cells involved in the immune response. Diabetes mellitus and uremia resulting
from kidney or liver disease are 2 common metabolic disorders with known deleterious
effects on immunity. Optimal control of the metabolic abnormality usually leads to
improved immune function. The defective immune functions reported in patients with
diabetes mellitus include defective phagocytosis and macrophage chemotaxis in vitro, T-cell
anergy demonstrated by delayed hypersensitivity skin tests, and poor lymphoproliferative
response to mitogens caused by chronic exposure to hyperglycemia.17 Impaired glucose
metabolism, insufficient blood supply, and denervation are other factors that contribute to
the increased susceptibility to infection in patients with diabetes, who present most
commonly with skin sores, bacterial and fungal respiratory tract infections, and systemic
viral diseases.

Uremic patients experience increased incidence and severity of infections compared with the
general population. Even when disparities in age, sex, race, and diabetes mellitus were taken
into account, mortality rates in patients undergoing dialysis attributed to sepsis were higher
by a factor of 100 to 300.18 The need for dialysis procedures and use of vascular devices are
independent risk factors for invasive infections. Multiple defects of the innate and adaptive
immunity have been described to have a role in the increased frequency of infections,
summarized as immune hyporesponsiveness and a state of chronic activation. The
diminished capacity to generate memory antibody responses, regardless of repeated
vaccination, and defective phagocyte chemotaxis and microbicidal activity in vitro are
examples of the immune defects present in uremic patients.
TABLE I.
Selected causes of secondary immunodeficiencies

Effect on
Condition
immune function

Extremes of age

Newborn period Immature lymphoid organs

Absent memory immunity
Low maternal IgG levels in
premature infants
Decreased neutrophil storage
pool
Decreased neutrophil function
Decreased natural killer
activity

Advanced age Decreased antigen-specific

cellular immunity
T-cell oligoclonality
Restricted B-cell repertoire
 Effect on
Condition
immune function

Malnutrition Decreased cellular immune

response
Weakened mucosal barriers

Metabolic diseases

Diabetes mellitus Decreased mitogen-induced

lymphoproliferation
Defective phagocytosis
Decreased chemotaxis

Chronic uremia Decreased cellular immune

response
Decreased generation of
memory antibody responses
Decreased chemotaxis

Genetic syndromes: trisomy 21 Defective phagocytosis

Defective chemotaxis
 Effect on
Condition
immune function

Variable defects of antigen-

specific immune responses

Anti-inflammatory, immunomodulatory, and Lymphopenia

immunosuppressive drug therapy: corticosteroids, calcineurin Decreased cellular immune
inhibitors, cytotoxic agents response and anergy
Decreased proinflammatory
cytokines
Decreased phagocytosis
Decreased chemotaxis
Neutropenia (cytotoxic
agents)
Weakened mucosal barriers
(cytotoxic agents)

Surgery and trauma Disruption of epithelial and

mucosal barriers
T-cell energy caused by
 Effect on
Condition
immune function

nonspecific immune
activation

Environmental conditions UV light, radiation, hypoxia, space lymphocyte apoptosis

Flight Increased secretion of
tolerogenic cytokines
Cytopenias
Decreased cellular immunity
and energy
Stress-induced nonspecific
immune activation

Infectious diseases: HIV infection T-cell lymphopenia

Decreased cellular immune
response and energy
Defective antigen-specific
antibody responses
Immunodeficiency and autoimmunity

There are a large number of immunodeficiency syndromes that present clinical and
laboratory characteristics of autoimmunity. The decreased ability of the immune system to
clear infections in these patients may be responsible for causing autoimmunity through
perpetual immune system activation.[12]

One example is common variable immunodeficiency (CVID) where multiple autoimmune

diseases are seen, e.g., inflammatory bowel disease, autoimmune thrombocytopenia, and
autoimmune thyroid disease. Familial hemophagocytic lymphohistiocytosis, an autosomal
recessive primary immunodeficiency, is another example. Low blood levels of red blood cells,
white blood cells, and platelets, rashes, lymph node enlargement, and enlargement of the
liver and spleen are commonly seen in these patients. Presence of multiple uncleared viral
infections due to lack of perforin are thought to be responsible. In addition to chronic
and/or recurrent infections many autoimmune diseases including arthritis, autoimmune
hemolytic anemia, scleroderma and type 1 diabetes are also seen in X-linked
agammaglobulinemia (XLA). Recurrent bacterial and fungal infections and chronic
inflammation of the gut and lungs are seen in chronic granulomatous disease (CGD) as
well. CGD is caused by a decreased production of nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase by neutrophils. Hypomorphic RAG mutations are seen in
patients with midline granulomatous disease; an autoimmune disorder that is commonly
seen in patients with granulomatosis with polyangiitis and NK/T cell lymphomas. Wiskott–
Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations,
recurrent bacterial infections and lymphoma. In autoimmune polyendocrinopathy-
candidiasis-ectodermal dystrophy (APECED) also autoimmunity and infections coexist:
organ-specific autoimmune manifestations (e.g., hypoparathyroidism and adrenocortical
failure) and chronic mucocutaneous candidiasis. Finally, IgA deficiency is also sometimes
associated with the development of autoimmune and atopic phenomena. Gene therapy in
Immunodeficiency
Causes

The cause of immunodeficiency varies depending on the nature of the disorder. The cause
can be either genetic or acquired by malnutrition and poor sanitary conditions.[13][14] Only
for some genetic causes, the exact genes are known.[15]

Treatment
Available treatment falls into two modalities: treating infections and boosting the immune
system.

Prevention of Pneumocystis pneumonia using trimethoprim/sulfamethoxazole is useful in

those who are immunocompromised.[16] In the early 1950s Immunoglobulin(Ig) was used by
doctors to treat patients with primary immunodeficiency through intramuscular injection.
Ig replacement therapy are infusions that can be either subcutaneous or intravenously
administrated, resulting in higher Ig levels for about three to four weeks, although this
varies with each patient.[11]
Prognosis
Prognosis depends greatly on the nature and severity of the condition. Some deficiencies
cause early mortality (before age one), others with or even without treatment are lifelong
conditions that cause little mortality or morbidity. Newer stem cell transplant technologies
may lead to gene based treatments of debilitating and fatal genetic immune deficiencies.
Prognosis of acquired immune deficiencies depends on avoiding or treating the causative
agent or condition (like AIDS).